US20190015379A1 - Use of dianhydrogalactitol and analogs and derivatives thereof, together with radiation, to treat non-small-cell carcinoma of the lung and glioblastoma multiforme and suppress proliferation of cancer stem cells - Google Patents

Use of dianhydrogalactitol and analogs and derivatives thereof, together with radiation, to treat non-small-cell carcinoma of the lung and glioblastoma multiforme and suppress proliferation of cancer stem cells Download PDF

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US20190015379A1
US20190015379A1 US15/525,933 US201515525933A US2019015379A1 US 20190015379 A1 US20190015379 A1 US 20190015379A1 US 201515525933 A US201515525933 A US 201515525933A US 2019015379 A1 US2019015379 A1 US 2019015379A1
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substituted hexitol
inhibitors
hexitol derivative
dianhydrogalactitol
antibodies
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Jeffrey A. Bacha
Dennis M. Brown
Anne Steinø
Shaun FOUSE
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Del Mar Pharmaceuticals BC Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the general field of hyperproliferative diseases including oncology with a focus on novel methods and compositions for the improved utility of chemical agents, compounds, and dosage forms previously limited by suboptimal human therapeutic performance including substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol, as well as other classes of chemical agents.
  • the present invention relates to the treatment of non-small-cell carcinoma of the lung with dianhydrogalactitol, diacetyldianhydrogalactitol, or derivatives or analogs thereof.
  • cancer is a collection of diseases with a multitude of etiologies and that a patient's response and survival from therapeutic intervention is complex with many factors playing a role in the success or failure of treatment including disease indication, stage of invasion and metastatic spread, patient gender, age, health conditions, previous therapies or other illnesses, genetic markers that can either promote or retard therapeutic efficacy, and other factors, the opportunity for cures in the near term remains elusive.
  • the incidence of cancer continues to rise with an approximate 4% increase predicted for 2003 in the United States by the American Cancer Society such that over 1.3 million new cancer cases are estimated.
  • diagnosis such as mammography for breast cancer and PSA tests for prostate cancer, more patients are being diagnosed at a younger age.
  • Non-small-cell lung carcinoma includes several types of lung cancer, including squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, as well as other types of lung cancer.
  • squamous cell carcinoma Although smoking is apparently the most frequent cause of squamous cell carcinoma, when lung cancer occurs in patients without any history of prior tobacco smoking, it is frequently adenocarcinoma.
  • NSCLC is refractory to chemotherapy, so surgical resection of the tumor mass is typically the treatment of choice, particularly if the malignancy is diagnosed early.
  • chemotherapy and radiation therapy are frequently attempted, particularly if the diagnosis cannot be made at an early stage of the malignancy.
  • Other treatments include radiofrequency ablation and chemoembolization.
  • chemotherapeutic treatments has been tried for advanced or metastatic NSCLC.
  • Some patients with particular mutations in the EGFR gene respond to EGFR tyrosine kinase inhibitors such as gefitinib (M. G. Kris, “How Today's Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow's Standards of Care,” Oncologist 10 (Suppl. 2): 23-29 (2005), incorporated herein by this reference).
  • Cisplatin has frequently been used as ancillary therapy together with surgery.
  • Erlotinib, pemetrexed, About 7% of NSCLC have EML4-ALK translocations, and such patients may benefit from ALK inhibitors such as crizotinib.
  • therapies including the vaccine TG4010, motesanib diphosphate, tivantinib, belotecan, eribulin mesylate, ramucirumab, necitumumab, the vaccine GSK1572932A, custirsen sodium, the liposome-based vaccine BLP25, nivolumab, EMD531444, dacomitinib, and genetespib, are being evaluated, particularly for advanced or metastatic NSCLC.
  • therapies against NSCLC should be well-tolerated and with side effects, if any, that could be easily controlled.
  • such therapies should be compatible with other chemotherapeutic approaches and with surgery or radiation. Additionally, and preferably, such therapies should be able to exert a synergistic effect on other treatment modalities. Additionally, there is a need for effective treatments for glioblastoma multiforme.
  • substituted hexitol derivative to treat non-small-cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) provides an improved therapy for NSCLC and GBM that yields increased survival and is substantially free of side effects.
  • the substituted hexitols usable in methods and compositions according to the present invention include galactitols, substituted galactitols, dulcitols, and substituted dulcitols.
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • a particularly preferred substituted hexitol derivative is dianhydrogalactitol (DAG).
  • DAG dianhydrogalactitol
  • the substituted hexitol derivative can be employed together with other therapeutic modalities for these malignancies.
  • Dianhydrogalactitol is particularly suited for the treatment of these malignancies because it can suppress the growth of cancer stem cells (CSC), and because it is resistant to drug inactivation by O 6 -methylguanine-DNA methyltransferase (MGMT).
  • CSC cancer stem cells
  • MGMT O 6 -methylguanine-DNA methyltransferase
  • the substituted hexitol derivative yields increased response rates and improved quality of life for patients with NSCLC and GBM.
  • Dianhydrogalactitol is a novel alkylating agent that creates N 7 -methylation in DNA. Specifically, the principal mechanism of action of dianhydrogalactitol is attributed to bi-functional N 7 DNA alkylation, via actual or derived epoxide groups, which cross-links across DNA strands.
  • one aspect of the present invention is a method to improve the efficacy and/or reduce the side effects of the administration of a substituted hexitol derivative for treatment of NSCLC and GBM comprising the steps of:
  • the factor or parameter is selected from the group consisting of:
  • CSC cancer stem cells
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the substituted hexitol derivative is dianhydrogalactitol.
  • compositions to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy employing a substituted hexitol derivative for the treatment of NSCLC comprising an alternative selected from the group consisting of:
  • a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage form wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage form possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC or GBM as compared with an unmodified substituted hexitol derivative;
  • a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage kit and packaging wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage kit and packaging possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC or GBM as compared with an unmodified substituted hexitol derivative;
  • a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is subjected to a bulk drug product improvement wherein substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative subjected to the bulk drug product improvement possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC or GBM as compared with an unmodified substituted hexitol derivative.
  • the unmodified substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the unmodified substituted hexitol derivative is dianhydrogalactitol.
  • Another aspect of the present invention is a method of treating NSCLC or GBM comprising the step of administering a therapeutically effective quantity of a substituted hexitol derivative to a patient suffering from NSCLC or GBM.
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the substituted hexitol derivative is dianhydrogalactitol.
  • the method can be used to treat patients who have developed resistance to tyrosine kinase inhibitors (TKI) or platinum-based chemotherapeutic agents such as cisplatin.
  • TKI tyrosine kinase inhibitors
  • platinum-based chemotherapeutic agents such as cisplatin.
  • the method can also be used together with TKI or platinum-based chemotherapeutic agents. Additionally, the method can also be used together with ionizing radiation or with agents that suppress the proliferation of cancer stem cells.
  • FIG. 1 is a graph that shows body weight on the y-axis versus days post-inoculation on the x-axis for the results of the Example.
  • • is the untreated control; ⁇ is the cisplatin control; ⁇ is dianhydrogalactitol at 1.5 mg/kg; ⁇ is dianhydrogalactitol at 3.0 mg/kg; and ⁇ is dianhydrogalactitol at 6.0 mg/kg.
  • FIG. 2 is a graph that shows the tumor volume (means ⁇ S.E.M.) for the A549 tumor-bearing female Rag2 mice with tumor volume on the y axis versus days post-inoculation on the x-axis for the results of the Example.
  • the top panel of FIG. 2 represents all mice for the complete duration of the study.
  • the bottom panel of FIG. 2 represents all mice until day 70 (last day for untreated control group).
  • FIG. 3 shows the mechanism of action for dianhydrogalactitol.
  • FIG. 4 shows the MGMT status of the cultures.
  • GPDH refers to glyceraldehyde-3-phosphate dehydrogenase as a control.
  • CSCs were cultured in NSA media supplemented with B27, EGF and bFGF.
  • Non-CSCs were grown in DMEM:F12 with 10% FBS.
  • MGMT methylation and protein expression analysis of each culture was characterized.
  • TMZ or VAL-083 was added to the cultures in the indicated concentrations.
  • cells were also irradiated with 2 Gy in a cesium irradiator.
  • cell cycle analysis was performed with Propidium Iodide staining and FACs analysis.
  • FIG. 4 Panel C shows the methylation status of MGMT for cell lines SF7996, SF8161, SF8279, and SF8565; “U” refers to unmethylated and “M” refers to methylated.
  • “1° GBM” refers to primary glioblastoma multiforme cell cultures.
  • FIG. 4 shows MGMT western blot analysis of protein extracts from 4 pairs of CSC and non-CSC cultures derived from primary GBM tissue.
  • FIG. 5 shows that dianhydrogalactitol (“VAL-083”) was better than TMZ for inhibiting tumor cell growth and that this occurred in an MGMT-independent manner.
  • FIG. 6 shows schematics of various treatment regimens for temozolomide (“TMZ”) or dianhydrogalactitol (“VAL”), with or without radiation (“XRT”).
  • TMZ temozolomide
  • VAL dianhydrogalactitol
  • XRT radiation
  • FIG. 7 shows cell cycle analyses for cancer stem cells (CSC) treated with TMZ or dianhydrogalactitol (“VAL-083”), for 7996 CSC, 8161 CSC, 8565 CSC, and 8279 CSC.
  • CSC cancer stem cells
  • VAL-083 dianhydrogalactitol
  • FIG. 8 shows cell cycle analyses for non-stem-cell cultures treated with TMZ or dianhydrogalactitol (“VAL-083”), for 7996 non-CSC, 8161 non-CSC, 8565 non-CSC, and U251.
  • VAL-083 TMZ or dianhydrogalactitol
  • FIG. 9 shows examples of FACS profiles for 7996 non-CSC dianhydrogalactitol (“VAL”) treatment.
  • FIG. 10 shows a schematic of the treatment regimen using either temozolomide (“TMZ”) or dianhydrogalactitol (“VAL”) and radiation (“XRT”).
  • TMZ temozolomide
  • VAL dianhydrogalactitol
  • XRT radiation
  • FIG. 11 shows results for 7996 CSC for TMZ only, VAL only, and TMZ or VAL with XRT.
  • TMZ “-D/-” indicates DMSO only (vehicle)
  • -T/- indicates TMZ only
  • -D/X or “-T/X” indicate DMSO or TMZ with XRT.
  • VAL “—P/-” indicates phosphate buffered saline (PBS) only (vehicle)
  • —V/-” indicates VAL only
  • “—P/X” or “—V/X” indicate PBS or VAL with XRT.
  • PBS phosphate buffered saline
  • FIG. 11 shows cell cycle analysis where G2 is shown at the top, S in the middle, and G1 at the bottom; both 4- and 6-day results are shown, with the 4-day results (“D4”) presented to the left of the 6-day results (“D6”).
  • D4 4-day results
  • D6 6-day results
  • the right side of FIG. 11 shows the results for cell viability as a percentage of control for D4 and D6.
  • FIG. 12 shows results for 8161 CSC depicted as in FIG. 11 .
  • FIG. 13 shows results for 8565 CSC depicted as in FIG. 11 .
  • FIG. 14 shows results for 7996 non-CSC depicted as in FIG. 11 .
  • FIG. 15 shows results for U251 depicted as in FIG. 11 .
  • FIG. 16 shows that dianhydrogalactitol causes cell cycle arrest in TMZ-resistant cultures.
  • TMZ dianhydrogalactitol
  • VAL-083 dianhydrogalactitol
  • FIG. 17 shows that dianhydrogalactitol decreases cell viability in TMZ-resistant cultures.
  • TMZ 50 ⁇ M
  • VAL-083 dianhydrogalactitol
  • FIG. 17 Shown are cell cycle profile analysis at day 4 post treatment (A,C) and cell viability analysis at day 6 post treatment (B,D) for the paired CSC (A,B) and non-CSC (C,D) 7996 culture. Whereas these cultures are not very sensitive to TMZ, they are to VAL-083.
  • FIG. 18 shows that dianhydrogalactitol acts as a radiosensitizer in primary CSC cultures.
  • dianhydrogalactitol (“VAL-083”) was added to primary CSC cultures at various doses (1, 2.5 and 5 ⁇ M) with or without irradiation (2 Gy). Shown are cell cycle profile analysis at day 4 post treatment (A,C) and cell viability analysis at day 6 post treatment (B,D) for two different patient-derived CSC cultures, 7996 (A,B) and 8565 (C,D).
  • FIG. 19 shows the treatment regimens with a wash or no wash for both dianhydrogalactitol and temozolomide.
  • FIG. 20 shows the results for 7996 GNS, showing cell cycle analysis where G2 is shown at the top, S in the middle, and G1 at the bottom. Results for TMZ are shown on the top and results for dianhydrogalactitol on the bottom. Results with a wash are shown on the left and results without a wash are shown on the right.
  • FIG. 21 shows the results for 8279 GNS, depicted as in FIG. 20 .
  • FIG. 22 shows the results for 7996 ML, depicted as in FIG. 20 .
  • FIG. 23 shows the results for 8565 ML, depicted as in FIG. 20 .
  • FIG. 24 shows the treatment regimens for combining dianhydrogalactitol (“VAL”) and radiation (“XRT”).
  • FIG. 25 shows the results for 7996 GNS (CSC) when dianhydrogalactitol is combined with radiation. Results are shown at day 4 (“D4”) on the top and day 6 (“D6”) on the bottom.
  • the left side shows cell cycle analysis where G2 is shown at the top, S in the middle, and G1 at the bottom.
  • the right side shows cell viability at D4 and D6.
  • FIG. 26 shows the results for 8565 GNS (CSC) as depicted in FIG. 25 .
  • FIG. 27 shows the results for 7996 ML (non-CSC) as depicted in FIG. 25 .
  • FIG. 28 shows the results for 8565 ML (non-CSC) as depicted in FIG. 25 .
  • FIG. 29 shows the activity of dianhydrogalactitol (VAL-083) and temozolomide (TMZ) in MGMT negative pediatric human GBM cell line SF188 (first panel), MGMT negative human GBM cell line U251 (second panel) and MGMT positive human GBM cell line T98G (third panel); immunoblots showing detection of MGMT and actin (as a control) in the individual cell lines are shown under the table providing the properties of the cell lines.
  • VAL-083 dianhydrogalactitol
  • TMZ temozolomide
  • FIG. 30 shows the plasma concentration-time profiles of dianhydrogalactitol showing dose-dependent systemic exposure (mean of 3 subjects per cohort).
  • DAG dianhydrogalactitol
  • NSCLC non-small-cell lung carcinoma
  • TMZ cisplatin
  • DAG can effectively suppress the growth of cancer stem cells (CSCs).
  • CSCs cancer stem cells
  • DAG acts independently of the MGMT repair mechanism. Therefore, DAG and derivatives or analogs thereof can be used to treat NSCLC or GBM.
  • dianhydrogalactitol (DAG) is shown in Formula (I), below.
  • substituted hexitols can be used in methods and compositions according to the present invention.
  • the substituted hexitols usable in methods and compositions according to the present invention include galactitols, substituted galacitols, dulcitols, and substituted dulcitols, including dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, and derivatives and analogs thereof.
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the substituted hexitol derivative is dianhydrogalactitol.
  • galactitols substituted galacitols, dulcitols, and substituted dulcitols are either alkylating agents or prodrugs of alkylating agents, as discussed further below.
  • derivatives of dianhydrogalactitol that, for example, have one or both hydrogens of the two hydroxyl groups of dianhydrogalactitol replaced with lower alkyl, have one or more of the hydrogens attached to the two epoxide rings replaced with lower alkyl, or have the methyl groups present in dianhydrogalactitol and that are attached to the same carbons that bear the hydroxyl groups replaced with C 2 -C 6 lower alkyl or substituted with, for example, halo groups by replacing a hydrogen of the methyl group with, for example a halo group.
  • halo group refers to one of fluoro, chloro, bromo, or iodo.
  • lower alkyl refers to C 1 -C 6 groups and includes methyl.
  • the term “lower alkyl” can be further limited, such as “C 2 -C 6 lower alkyl,” which excludes methyl.
  • the term “lower alkyl”, unless further limited, refers to both straight-chain and branched alkyl groups. These groups can, optionally, be further substituted, as described below.
  • derivatives of diacetyldianhydrogalactitol that, for example, have one or both of the methyl groups that are part of the acetyl moieties replaced with C 2 -C 6 lower alkyl, have one or both of the hydrogens attached to the epoxide ring replaced with lower alkyl, or have the methyl groups attached to the same carbons that bear the acetyl groups replaced with lower alkyl or substituted with, for example, halo groups by replacing a hydrogen with, for example, a halo group.
  • dibromodulcitol The structure of dibromodulcitol is shown in Formula (III), below.
  • Dibromodulcitol can be produced by the reaction of dulcitol with hydrobromic acid at elevated temperatures, followed by crystallization of the dibromodulcitol.
  • Some of the properties of dibromodulcitol are described in N. E. Mischler et al., “Dibromoducitol,” Cancer Treat. Rev. 6: 191-204 (1979), incorporated herein by this reference.
  • dibromodulcitol as an ⁇ , ⁇ -dibrominated hexitol
  • dibromodulcitol shares many of the biochemical and biological properties of similar drugs such as dibromomannitol and mannitol myleran.
  • dibromodulcitol Activation of dibromodulcitol to the diepoxide dianhydrogalactitol occurs in vivo, and dianhydrogalactitol may represent a major active form of the drug; this means that dibromogalactitol has many of the properties of a prodrug. Absorption of dibromodulcitol by the oral route is rapid and fairly complete. Dibromodulcitol has known activity in melanoma, breast lymphoma (both Hodgkins and non-Hodgkins), colorectal cancer, acute lymphoblastic leukemia and has been shown to lower the incidence of central nervous system leukemia, non-small cell lung cancer, cervical carcinoma, bladder carcinoma, and metastatic hemangiopericytoma.
  • derivatives of dibromodulcitol that, for example, have one or more hydrogens of the hydroxyl groups replaced with lower alkyl, or have one or both of the bromo groups replaced with another halo group such as chloro, fluoro, or iodo.
  • substituents at saturated carbon atoms such as those that are part of the structures of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol
  • substituents can be employed: C 6 -C 10 aryl, heteroaryl containing 1-4 heteroatoms selected from N, O, and S, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, cycloalkyl, F, amino (NR 1 R 2 ), nitro, —SR, —S(O)R, —S(O 2 )R, —S(O 2 )NR 1 R 2 , and —CONR 1 R 2 , which can in turn be optionally substituted. Further descriptions of potential optional substituents are provided below.
  • Optional substituents as described above that are within the scope of the present invention do not substantially affect the activity of the derivative or the stability of the derivative, particularly the stability of the derivative in aqueous solution.
  • Definitions for a number of common groups that can be used as optional substituents are provided below; however, the omission of any group from these definitions cannot be taken to mean that such a group cannot be used as an optional substituent as long as the chemical and pharmacological requirements for an optional substituent are satisfied.
  • alkyl refers to an unbranched, branched, or cyclic saturated hydrocarbyl residue, or a combination thereof, of from 1 to 12 carbon atoms that can be optionally substituted; the alkyl residues contain only C and H when unsubstituted.
  • the unbranched or branched saturated hydrocarbyl residue is from 1 to 6 carbon atoms, which is referred to herein as “lower alkyl.”
  • the hydrocarbyl residue includes at least three carbon atoms, which is the minimum number to form a ring.
  • alkenyl refers to an unbranched, branched or cyclic hydrocarbyl residue having one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched, branched, or cyclic hydrocarbyl residue having one or more carbon-carbon triple bonds; the residue can also include one or more double bonds. With respect to the use of “alkenyl” or “alkynyl,” the presence of multiple double bonds cannot produce an aromatic ring.
  • hydroxyalkyl refers to an alkyl, alkenyl, or alkynyl group including one or more hydroxyl groups as substituents; as detailed below, further substituents can be optionally included.
  • aryl refers to a monocyclic or fused bicyclic moiety having the well-known characteristics of aromaticity; examples include phenyl and naphthyl, which can be optionally substituted.
  • hydroxyaryl refers to an aryl group including one or more hydroxyl groups as substituents; as further detailed below, further substituents can be optionally included.
  • heteroaryl refers to monocyclic or fused bicyclic ring systems that have the characteristics of aromaticity and include one or more heteroatoms selected from O, S, and N. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as in 6-membered rings.
  • Typical heteroaromatic systems include monocyclic C 5 -C 6 heteroaromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, and imidazolyl, as well as the fused bicyclic moieties formed by fusing one of these monocyclic heteroaromatic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C 8 -C 10 bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolylpyridyl, quinazolinyl, quinoxalin
  • any monocyclic or fused ring bicyclic system that has the characteristics of aromaticity in terms of delocalized electron distribution throughout the ring system is included in this definition.
  • This definition also includes bicyclic groups where at least the ring that is directly attached to the remainder of the molecule has the characteristics of aromaticity, including the delocalized electron distribution that is characteristic of aromaticity.
  • the ring systems contain 5 to 12 ring member atoms and up to four heteroatoms, wherein the heteroatoms are selected from the group consisting of N, O, and S.
  • the monocyclic heteroaryls contain 5 to 6 ring members and up to three heteroatoms selected from the group consisting of N, O, and S; frequently, the bicyclic heteroaryls contain 8 to 10 ring members and up to four heteroatoms selected from the group consisting of N, O, and S.
  • the number and placement of heteroatoms in heteroaryl ring structures is in accordance with the well-known limitations of aromaticity and stability, where stability requires the heteroaromatic group to be stable enough to be exposed to water at physiological temperatures without rapid degradation.
  • the term “hydroxheteroaryl” refers to a heteroaryl group including one or more hydroxyl groups as substituents; as further detailed below, further substituents can be optionally included.
  • haloaryl and haloheteroaryl refer to aryl and heteroaryl groups, respectively, substituted with at least one halo group, where “halo” refers to a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included.
  • haloalkyl refers to alkyl, alkenyl, and alkynyl groups, respectively, substituted with at least one halo group
  • halo refers to a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included.
  • optionally substituted indicates that the particular group or groups referred to as optionally substituted may have no non-hydrogen substituents, or the group or groups may have one or more non-hydrogen substituents consistent with the chemistry and pharmacological activity of the resulting molecule. If not otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present on the unsubstituted form of the group being described; fewer than the maximum number of such substituents may be present.
  • the group takes up two available valences on the carbon atom to which the optional substituent is attached, so the total number of substituents that may be included is reduced according to the number of available valiences.
  • substituted whether used as part of “optionally substituted” or otherwise, when used to modify a specific group, moiety, or radical, means that one or more hydrogen atoms are, each, independently of each other, replaced with the same or different substituent or substituents.
  • Substituent groups useful for substituting saturated carbon atoms in the specified group, moiety, or radical include, but are not limited to, —Z a , ⁇ O, —OZ b , —SZ b , ⁇ S ⁇ , —NZ c Z c , ⁇ NZ b , ⁇ N—OZ b , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , ⁇ N 2 , —N 3 , —S(O) 2 Z b , —S(O) 2 NZ b , —S(O 2 )O ⁇ , —S(O 2 )OZ b , —OS(O 2 )OZ b , —OS(O 2 )OZ b , —OS(O 2 )O ⁇ , —OS(O 2 )OZ b , —P(
  • —NZ c Z c is meant to include —NH 2 , —NH-alkyl, —N-pyrrolidinyl, and —N-morpholinyl, but is not limited to those specific alternatives and includes other alternatives known in the art.
  • a substituted alkyl is meant to include -alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroaryl, -alkylene-C(O)OZ b , -alkylene-C(O)NZ b Z b , and —CH 2 —CH 2 —C(O)—CH 3 , but is not limited to those specific alternatives and includes other alternatives known in the art.
  • the one or more substituent groups, together with the atoms to which they are bonded, may form a cyclic ring, including, but not limited to, cycloalkyl and cycloheteroalkyl.
  • substituent groups useful for substituting unsaturated carbon atoms in the specified group, moiety, or radical include, but are not limited to, —Z a , halo, —O ⁇ , —OZ b , —SZ b , —S ⁇ , —NZ c Z c , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 Z b , —S(O 2 )O ⁇ , —S(O 2 )OZ b , —OS(O 2 )OZ b , —OS(O 2 )O ⁇ , —P(O)(O ⁇ ) 2 , —P(O)(OZ b )(O ⁇ ), —P(O)(OZ b )(OZ b ), —C(O)Z
  • substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, —Z a , halo, —O ⁇ , —OZ b , —SZ b , —S ⁇ , —NZ c Z c , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —S(O) 2 Z b , —S(O 2 )O ⁇ , —S(O 2 )OZ b , —OS(O 2 )OZ b , —OS(O 2 )O ⁇ , —P(O)(O ⁇ ) 2 , —P(O)(OZ b )(O ⁇ ), —P(O)(OZ b )(OZ b ), —C(O)Z b
  • the compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers such as E and Z), enantiomers or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers such as E and Z), enantiomers or diastereomers.
  • the invention includes each of the isolated stereoisomeric forms (such as the enantiomerically pure isomers, the E and Z isomers, and other alternatives for stereoisomers) as well as mixtures of stereoisomers in varying degrees of chiral purity or percentage of E and Z, including racemic mixtures, mixtures of diastereomers, and mixtures of E and Z isomers.
  • the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the invention includes each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers.
  • the compounds may also exist in several tautomeric forms, and the depiction herein of one tautomer is for convenience only, and is also understood to encompass other tautomers of the form shown. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • tautomer refers to isomers that change into one another with great ease so that they can exist together in equilibrium; the equilibrium may strongly favor one of the tautomers, depending on stability considerations. For example, ketone and enol are two tautomeric forms of one compound.
  • solvate means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound of the invention, with one or more solvent molecules.
  • solvate When water is the solvent, the corresponding solvate is “hydrate.” Examples of hydrate include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other water-containing species. It should be understood by one of ordinary skill in the art that the pharmaceutically acceptable salt, and/or prodrug of the present compound may also exist in a solvate form.
  • the solvate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the anhydrous compound of the present invention.
  • esters means any ester of a present compound in which any of the —COOH functions of the molecule is replaced by a —COOR function, in which the R moiety of the ester is any carbon-containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof.
  • the hydrolysable esters of the present compounds are the compounds whose carboxyls are present in the form of hydrolysable ester groups. That is, these esters are pharmaceutically acceptable and can be hydrolyzed to the corresponding carboxyl acid in vivo.
  • alkyl, alkenyl and alkynyl groups can alternatively or in addition be substituted by C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, or C 5 -C 10 heteroaryl, each of which can be optionally substituted.
  • the two groups capable of forming a ring having 5 to 8 ring members are present on the same or adjacent atoms, the two groups can optionally be taken together with the atom or atoms in the substituent groups to which they are attached to form such a ring.
  • Heteroalkyl “heteroalkenyl,” and “heteroalkynyl” and the like are defined similarly to the corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the ‘hetero’ terms refer to groups that contain 1-3 O, S or N heteroatoms or combinations thereof within the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the specified heteroatoms to form, respectively, a heteroalkyl, heteroalkenyl, or heteroalkynyl group.
  • such groups do not include more than two contiguous heteroatoms except where an oxo group is present on N or S as in a nitro or sulfonyl group.
  • alkyl as used herein includes cycloalkyl and cycloalkylalkyl groups
  • the term “cycloalkyl” may be used herein to describe a carbocyclic non-aromatic group that is connected via a ring carbon atom
  • cycloalkylalkyl may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker.
  • heterocyclyl may be used to describe a non-aromatic cyclic group that contains at least one heteroatom (typically selected from N, O and S) as a ring member and that is connected to the molecule via a ring atom, which may be C (carbon-linked) or N (nitrogen-linked); and “heterocyclylalkyl” may be used to describe such a group that is connected to another molecule through a linker.
  • the heterocyclyl can be fully saturated or partially saturated, but non-aromatic.
  • the sizes and substituents that are suitable for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups.
  • the heterocyclyl groups typically contain 1, 2 or 3 heteroatoms, selected from N, O and S as ring members; and the N or S can be substituted with the groups commonly found on these atoms in heterocyclic systems. As used herein, these terms also include rings that contain a double bond or two, as long as the ring that is attached is not aromatic.
  • the substituted cycloalkyl and heterocyclyl groups also include cycloalkyl or heterocyclic rings fused to an aromatic ring or heteroaromatic ring, provided the point of attachment of the group is to the cycloalkyl or heterocyclyl ring rather than to the aromatic/heteroaromatic ring.
  • acyl encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one of the two available valence positions of a carbonyl carbon atom
  • heteroacyl refers to the corresponding groups wherein at least one carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from N, O and S.
  • Acyl and heteroacyl groups are bonded to any group or molecule to which they are attached through the open valence of the carbonyl carbon atom. Typically, they are C 1 -C 8 acyl groups, which include formyl, acetyl, pivaloyl, and benzoyl, and C 2 -C 8 heteroacyl groups, which include methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl.
  • arylalkyl and “heteroarylalkyl” refer to aromatic and heteroaromatic ring systems which are bonded to their attachment point through a linking group such as an alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers.
  • the linker is C 1 -C 8 alkyl.
  • These linkers may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety.
  • An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group may be substituted with the same substituents described above for aryl groups.
  • an arylalkyl group includes a phenyl ring optionally substituted with the groups defined above for aryl groups and a C 1 -C 4 alkylene that is unsubstituted or is substituted with one or two C 1 -C 4 alkyl groups or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
  • a heteroarylalkyl group preferably includes a C 5 -C 6 monocyclic heteroaryl group that is optionally substituted with the groups described above as substituents typical on aryl groups and a C 1 -C 4 alkylene that is unsubstituted or is substituted with one or two C 1 -C 4 alkyl groups or heteroalkyl groups, or it includes an optionally substituted phenyl ring or C 5 -C 6 monocyclic heteroaryl and a C 1 -C 4 heteroalkylene that is unsubstituted or is substituted with one or two C 1 -C 4 alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
  • substituents may be on either the alkyl or heteroalkyl portion or on the aryl or heteroaryl portion of the group.
  • the substituents optionally present on the alkyl or heteroalkyl portion are the same as those described above for alkyl groups generally; the substituents optionally present on the aryl or heteroaryl portion are the same as those described above for aryl groups generally.
  • Arylalkyl groups as used herein are hydrocarbyl groups if they are unsubstituted, and are described by the total number of carbon atoms in the ring and alkylene or similar linker. Thus a benzyl group is a C7-arylalkyl group, and phenylethyl is a C8-arylalkyl.
  • Heteroarylalkyl refers to a moiety comprising an aryl group that is attached through a linking group, and differs from “arylalkyl” in that at least one ring atom of the aryl moiety or one atom in the linking group is a heteroatom selected from N, O and S.
  • the heteroarylalkyl groups are described herein according to the total number of atoms in the ring and linker combined, and they include aryl groups linked through a heteroalkyl linker; heteroaryl groups linked through a hydrocarbyl linker such as an alkylene; and heteroaryl groups linked through a heteroalkyl linker.
  • C7-heteroarylalkyl would include pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.
  • Alkylene refers to a divalent hydrocarbyl group; because it is divalent, it can link two other groups together. Typically it refers to —(CH 2 ) n — where n is 1-8 and preferably n is 1-4, though where specified, an alkylene can also be substituted by other groups, and can be of other lengths, and the open valences need not be at opposite ends of a chain.
  • any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group that is contained in a substituent may itself optionally be substituted by additional substituents.
  • the nature of these substituents is similar to those recited with regard to the primary substituents themselves if the substituents are not otherwise described.
  • “Amino” as used herein refers to —NH 2 , but where an amino is described as “substituted” or “optionally substituted”, the term includes NR′R′′ wherein each R′ and R′′ is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl groups is optionally substituted with the substituents described herein as suitable for the corresponding group; the R′ and R′′ groups and the nitrogen atom to which they are attached can optionally form a 3- to 8-membered ring which may be saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S as ring members, and which is optionally substituted with the substituents described as suitable for alkyl groups or, if NR′R′′ is an aromatic group, it is optionally substituted with
  • the term “carbocycle,” “carbocyclyl,” or “carbocyclic” refers to a cyclic ring containing only carbon atoms in the ring, whereas the term “heterocycle” or “heterocyclic” refers to a ring comprising a heteroatom.
  • the carbocyclyl can be fully saturated or partially saturated, but non-aromatic.
  • the carbocyclyl encompasses cycloalkyl.
  • the carbocyclic and heterocyclic structures encompass compounds having monocyclic, bicyclic or multiple ring systems; and such systems may mix aromatic, heterocyclic, and carbocyclic rings. Mixed ring systems are described according to the ring that is attached to the rest of the compound being described.
  • heteroatom refers to any atom that is not carbon or hydrogen, such as nitrogen, oxygen or sulfur. When it is part of the backbone or skeleton of a chain or ring, a heteroatom must be at least divalent, and will typically be selected from N, O, P, and S.
  • alkanoyl refers to an alkyl group covalently linked to a carbonyl (C ⁇ O) group.
  • lower alkanoyl refers to an alkanoyl group in which the alkyl portion of the alkanoyl group is C 1 -C 6 .
  • the alkyl portion of the alkanoyl group can be optionally substituted as described above.
  • alkylcarbonyl can alternatively be used.
  • alkenylcarbonyl and alkynylcarbonyl refer to an alkenyl or alkynyl group, respectively, linked to a carbonyl group.
  • alkoxy refers to an alkyl group covalently linked to an oxygen atom; the alkyl group can be considered as replacing the hydrogen atom of a hydroxyl group.
  • lower alkoxy refers to an alkoxy group in which the alkyl portion of the alkoxy group is C 1 -C 6 .
  • the alkyl portion of the alkoxy group can be optionally substituted as described above.
  • haloalkoxy refers to an alkoxy group in which the alkyl portion is substituted with one or more halo groups.
  • sulfo refers to a sulfonic acid (—SO 3 H) substituent.
  • sulfamoyl refers to a substituent with the structure —S(O 2 )NH 2 , wherein the nitrogen of the NH 2 portion of the group can be optionally substituted as described above.
  • carboxyl refers to a group of the structure —C(O 2 )H.
  • carbamyl refers to a group of the structure —C(O 2 )NH 2 , wherein the nitrogen of the NH 2 portion of the group can be optionally substituted as described above.
  • the terms “monoalkylaminoalkyl” and “dialkylaminoalkyl” refer to groups of the structure -Alk 1 -NH-Alk 2 and -Alk 1 -N(Alk 2 )(Alk 3 ), wherein Alk 1 , Alk 2 , and Alk 3 refer to alkyl groups as described above.
  • alkylsulfonyl refers to a group of the structure —S(O) 2 -Alk wherein Alk refers to an alkyl group as described above.
  • alkenylsulfonyl and alkynylsulfonyl refer analogously to sulfonyl groups covalently bound to alkenyl and alkynyl groups, respectively.
  • arylsulfonyl refers to a group of the structure —S(O) 2 —Ar wherein Ar refers to an aryl group as described above.
  • aryloxyalkylsulfonyl refers to a group of the structure —S(O) 2 -Alk-O—Ar, where Alk is an alkyl group as described above and Ar is an aryl group as described above.
  • arylalkylsulfonyl refers to a group of the structure —S(O) 2 -AlkAr, where Alk is an alkyl group as described above and Ar is an aryl group as described above.
  • alkyloxycarbonyl refers to an ester substituent including an alkyl group wherein the carbonyl carbon is the point of attachment to the molecule.
  • An example is ethoxycarbonyl, which is CH 3 CH 2 OC(O)—.
  • alkenyloxycarbonyl,” “alkynyloxycarbonyl,” and “cycloalkylcarbonyl” refer to similar ester substituents including an alkenyl group, alkenyl group, or cycloalkyl group respectively.
  • aryloxycarbonyl refers to an ester substituent including an aryl group wherein the carbonyl carbon is the point of attachment to the molecule.
  • aryloxyalkylcarbonyl refers to an ester substituent including an alkyl group wherein the alkyl group is itself substituted by an aryloxy group.
  • substituents are known in the art and, are described, for example, in U.S. Pat. No. 8,344,162 to Jung et al., incorporated herein by this reference.
  • thiocarbonyl and combinations of substituents including “thiocarbonyl” include a carbonyl group in which a double-bonded sulfur replaces the normal double-bonded oxygen in the group.
  • alkylidene and similar terminology refer to an alkyl group, alkenyl group, alkynyl group, or cycloalkyl group, as specified, that has two hydrogen atoms removed from a single carbon atom so that the group is double-bonded to the remainder of the structure.
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol, unless otherwise specified.
  • the substituted hexitol derivative is dianhydrogalactitol, unless otherwise specified.
  • derivatives of dianhydrogalactitol such as compound analogs or prodrugs are preferred, as stated below.
  • the term “antibody” encompasses both polyclonal and monoclonal antibodies, as well as genetically engineered antibodies such as chimeric, humanized or fully human antibodies of the appropriate binding specificity. As used herein, unless further defined, the term “antibody” also encompasses antibody fragments such as sFv, Fv, Fab, Fab′ and F(ab)′ 2 fragments. In many cases, it is preferred to use monoclonal antibodies. In some contexts, antibodies can include fusion proteins comprising an antigen-binding site of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site (i.e., antigen-binding site) as long as the antibodies exhibit the desired biological activity.
  • An antibody can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively.
  • the different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations.
  • Antibodies can be naked or conjugated to other molecules, including but not limited to, toxins, antineoplastic agents, antimetabolites, or radioisotopes; in some cases, conjugation occurs through a linker or through noncovalent interactions such as an avidin-biotin or streptavidin-biotin linkage.
  • antibody fragment refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody.
  • antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, and Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies formed from antibody fragments.
  • Antibody fragment as used herein comprises an antigen-binding site or epitope-binding site.
  • variable region of an antibody refers to the variable region of an antibody light chain, or the variable region of an antibody heavy chain, either alone or in combination.
  • variable regions of the heavy and light chains each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs), also known as “hypervariable regions.”
  • CDRs complementarity determining regions
  • the CDRs in each chain are held together in close proximity by the framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of the antibody.
  • CDRs There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Edition, National Institutes of Health, Bethesda, Md.), and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948). In addition, combinations of these two approaches are sometimes used in the art to determine CDRs.
  • the term “monoclonal antibody” as used herein refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope.
  • polyclonal antibodies that typically include a mixture of different antibodies directed against a variety of different antigenic determinants.
  • the term “monoclonal antibody” encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (e.g., Fab, Fab′, F(ab′)2, Fv), single chain (sFv) antibodies, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site (antigen-binding site).
  • monoclonal antibody refers to such antibodies made by any number of techniques, including but not limited to, hybridoma production, phage selection, recombinant expression, and expression in transgenic animals.
  • humanized antibody refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human sequences.
  • humanized antibodies are human immunoglobulins in which residues of the CDRs are replaced by residues from the CDRs of a non-human species (e.g., mouse, rat, rabbit, or hamster) that have the desired specificity, affinity, and/or binding capability (Jones et al., 1986, Nature, 321:522-525; Riechmann et al., 1988, Nature, 332:323-327; Verhoeyen et al., 1988, Science, 239:1534-1536).
  • a non-human species e.g., mouse, rat, rabbit, or hamster
  • the Fv framework region residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and/or binding capability.
  • the humanized antibody can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or binding capability.
  • the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDRs that correspond to the non-human immunoglobulin whereas all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region or domain
  • Examples of methods used to generate humanized antibodies are described in, for example, U.S. Pat. No. 5,225,539.
  • the term “human antibody” as used herein refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human.
  • a human antibody may be made using any of the techniques known in the art. This definition of a human antibody specifically excludes a humanized antibody comprising non-human CDRs.
  • chimeric antibody refers to an antibody wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species.
  • variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, or other antibody producing mammal) with the desired specificity, affinity, and/or binding capability, while the constant regions correspond to sequences in antibodies derived from another species (usually human).
  • mammals e.g., mouse, rat, rabbit, or other antibody producing mammal
  • constant regions correspond to sequences in antibodies derived from another species (usually human).
  • epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a protein.
  • Epitopes formed from contiguous amino acids are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding (also referred to as conformational epitopes) are typically lost upon protein denaturing.
  • An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.
  • antagonists refer to any molecule that partially or fully blocks, inhibits, reduces, or neutralizes a biological activity of a target and/or signaling pathway, or that partially or fully blocks, inhibits, reduces, or neutralizes the activity of a protein.
  • Suitable antagonist molecules specifically include, but are not limited to, antagonist antibodies or antibody fragments.
  • agonist refers to any molecule that partially or fully promotes, activates, or accelerates a biological activity of a target and/or signaling pathway or the activity of a protein, or that overcomes antagonism.
  • modulation and modulate refer to a change or an alteration in a biological activity.
  • Modulation includes, but is not limited to, stimulating or inhibiting an activity. Modulation may be an increase or a decrease in activity, a change in binding characteristics, or any other change in the biological, functional, or immunological properties associated with the activity of a protein, pathway, or other biological point of interest.
  • the terms “selectively binds” or “specifically binds” mean that a binding agent or an antibody reacts or associates more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope, protein, or target molecule than with alternative substances, including unrelated proteins.
  • “specifically binds” means, for instance, that an antibody binds a protein with a K D of about 0.1 mM or less, but more usually less than about 1 ⁇ M. In certain embodiments, “specifically binds” means that an antibody binds a target at times with a K D of at least about 0.1 ⁇ M or less, at other times at least about 0.01 ⁇ M or less, and at other times at least about 1 nM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include an antibody that recognizes a protein in more than one species.
  • specific binding can include an antibody (or other polypeptide or binding agent) that recognizes more than one protein. It is understood that, in certain embodiments, an antibody or binding moiety that specifically binds a first target may or may not specifically bind a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, i.e. binding to a single target. Thus, an antibody may, in certain embodiments, specifically bind more than one target. In certain embodiments, multiple targets may be bound by the same antigen-binding site on the antibody.
  • an antibody may, in certain instances, comprise two identical antigen-binding sites, each of which specifically binds the same epitope on two or more proteins.
  • an antibody may be multispecific and comprise at least two antigen-binding sites with differing specificities.
  • a bispecific antibody may comprise one antigen-binding site that recognizes an epitope on one protein and further comprise a second, different antigen-binding site that recognizes a different epitope on a second protein.
  • reference to binding means specific binding.
  • analogue refers to a chemical compound that is structurally similar to a parent compound, but differs slightly in composition (e.g., one atom or functional group is different, added, or removed).
  • the analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity.
  • the analogue may be more hydrophilic or hydrophobic or it may have altered reactivity as compared to the parent compound.
  • the analogue may mimic the chemical and/or biologically activity of the parent compound (i.e., it may have similar or identical activity), or, in some cases, may have increased or decreased activity.
  • the analogue may be a naturally or non-naturally occurring variant of the original compound.
  • Other types of analogues include isomers (enantiomers, diastereomers, and the like) and other types of chiral variants of a compound, as well as structural isomers.
  • “derivative” refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound.
  • a “derivative” differs from an “analogue” in that a parent compound may be the starting material to generate a “derivative,” whereas the parent compound may not necessarily be used as the starting material to generate an “analogue.”
  • a derivative may or may not have different chemical or physical properties of the parent compound. For example, the derivative may be more hydrophilic or hydrophobic or it may have altered reactivity as compared to the parent compound.
  • Derivatization may involve substitution of one or more moieties within the molecule (e.g., a change in functional group).
  • derivative also includes conjugates and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions).
  • a description of a compound includes salts and solvates, including hydrates, of the compound unless specifically excluded.
  • One aspect of the present invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations to the time that the compound is administered, the use of dose-modifying agents that control the rate of metabolism of the compound, normal tissue protective agents, and other alterations.
  • General examples include: variations of infusion schedules (e.g., bolus i.v.
  • lymphokines e.g., G-CSF, GM-CSF, EPO
  • lymphokines e.g., G-CSF, GM-CSF, EPO
  • rescue agents such as leucovorin for 5-FU or thiosulfate for cisplatin treatment.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: continuous i.v.
  • Another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the route by which the compound is administered.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: changing route from oral to intravenous administration and vice versa; or the use of specialized routes such as subcutaneous, intramuscular, intraarterial, intraperitoneal, intralesional, intralymphatic, intratumoral, intrathecal, intravesicular, intracranial.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC include: topical administration; oral administration; slow-release oral delivery; intrathecal administration; intraarterial administration; continuous infusion; intermittent infusion; intravenous administration; or administration through a longer infusion; or administration through IV push.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol made by changes in the schedule of administration.
  • General examples include: daily administration, biweekly administration, or weekly administration.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: daily administration; weekly administration; weekly administration for three weeks; biweekly administration; biweekly administration for three weeks with a 1-2 week rest period; intermittent boost dose administration; or daily administration for one week for multiple weeks.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the stage of disease at diagnosis/progression that the compound is administered.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: the use of chemotherapy for non-resectable local disease, prophylactic use to prevent metastatic spread or inhibit disease progression or conversion to more malignant stages.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use in an appropriate disease stage for NSCLC; use of the substituted hexitol derivative such as dianhydrogalactitol with angiogenesis inhibitors such as AvastinTM, a VEGF inhibitor, to prevent or limit metastatic spread; the use of a substituted hexitol derivative such as dianhydrogalactitol for newly diagnosed disease; the use of a substituted hexitol derivative such as dianhydrogalactitol for recurrent disease; or the use of a substituted hexitol derivative such as dianhydrogalactitol for resistant or refractory disease.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations to the type of patient that would best tolerate or benefit from the use of the compound.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: use of pediatric doses for elderly patients, altered doses for obese patients; exploitation of co-morbid disease conditions such as diabetes, cirrhosis, or other conditions that may uniquely exploit a feature of the compound.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: patients with a disease condition characterized by a high level of a metabolic enzyme selected from the group consisting of histone deacetylase and ornithine decarboxylase; patients with a low or high susceptibility to a condition selected from the group consisting of thrombocytopenia and neutropenia; patients intolerant of GI toxicities; patients characterized by over- or under-expression of a gene selected from the group consisting of c-Jun, a GPCR, a signal transduction protein, VEGF, a prostate-specific gene, and a protein kinase; prostate-specific gene, and a protein kinase; patients characterized by a mutation in EGFR including, but not limited to, EGFR Variant III; patients being administered a platinum-based drug as combination therapy; patients who do not have EGFR mutations and thus are less likely to respond to
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by more precise identification of a patient's ability to tolerate, metabolize and exploit the use of the compound as associated with a particular phenotype of the patient.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: use of diagnostic tools and kits to better characterize a patient's ability to process/metabolize a chemotherapeutic agent or the susceptibility of the patient to toxicity caused by potential specialized cellular, metabolic, or organ system phenotypes.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use of a diagnostic tool, a diagnostic technique, a diagnostic kit, or a diagnostic assay to confirm a patient's particular phenotype; use of a method for measurement of a marker selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, a protein that is a gene product of jun, and a protein kinase; surrogate compound testing; or low dose pre-testing for enzymatic status.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by more precise identification of a patient's ability to tolerate, metabolize and exploit the use of the compound as associated with a particular genotype of the patient.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • biopsy samples of tumors or normal tissues e.g., glial cells or other cells of the central nervous system
  • SNP's single nucleotide polymorphisms
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: diagnostic tools, techniques, kits and assays to confirm a patient's particular genotype; gene/protein expression chips and analysis; Single Nucleotide Polymorphisms (SNP's) assessment; SNP's for histone deacetylase, ornithine decarboxylase, GPCR's, protein kinases, telomerase, or jun; identification and measurement of metabolism enzymes and metabolites; determination of mutation of PDGFRA gene; determination of mutation of IDH1 gene; determination of mutation of NF1 gene; determination of copy number of the EGFR gene; determination of status of methylation of promoter of MGMT gene; use for disease characterized by an unmethylated promoter region of the MGMT gene; use for disease characterized by a methylated promoter region of the MGMT gene; use for disease characterized by high expression of MGMT; use for disease characterized
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by specialized preparation of a patient prior to or after the use of a chemotherapeutic agent.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: induction or inhibition of metabolizing enzymes, specific protection of sensitive normal tissues or organ systems.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of colchicine or analogs; use of diuretics such as probenecid; use of a uricosuric; use of uricase; non-oral use of nicotinamide; sustained release forms of nicotinamide; use of inhibitors of poly (ADP ribose) polymerase; use of caffeine; leucovorin rescue; infection control; antihypertensives.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by use of additional drugs or procedures to prevent or reduce potential side-effects or toxicities.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • additional drugs or procedures to prevent or reduce potential side-effects or toxicities.
  • General examples include: the use of anti-emetics, anti-nausea, hematological support agents to limit or prevent neutropenia, anemia, thrombocytopenia, vitamins, antidepressants, treatments for sexual dysfunction, and other supportive techniques.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of colchicine or analogs; use of diuretics such as probenecid; use of a uricosuric; use of uricase; non-oral use of nicotinamide; use of sustained release forms of nicotinamide; use of inhibitors of poly ADP-ribose polymerase; use of caffeine; leucovorin rescue; use of sustained release allopurinol; non-oral use of allopurinol; use of bone marrow transplants; use of a blood cell stimulant; use of blood or platelet infusions; use of filgrastim, G-CSF, or GM-CSF; use of pain management techniques; use of anti-inflammatories; use of fluids; use of corticosteroids; use of insulin control medications; use of antipyretics; use of anti-nausea treatments; use of anti-diar
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by the use of monitoring drug levels after dosing in an effort to maximize a patient's drug plasma level, to monitor the generation of toxic metabolites, monitoring of ancillary medicines that could be beneficial or harmful in terms of drug-drug interactions.
  • General examples include: the monitoring of drug plasma protein binding, and monitoring of other pharmacokinetic or pharmacodynamic variables.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: multiple determinations of drug plasma levels; or multiple determinations of metabolites in the blood or urine.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by exploiting unique drug combinations that may provide a more than additive or synergistic improvement in efficacy or side-effect management.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use with topoisomerase inhibitors; use with fraudulent nucleosides; use with fraudulent nucleotides; use with thymidylate synthetase inhibitors; use with signal transduction inhibitors; use with cisplatin or platinum analogs; use with alkylating agents such as the nitrosoureas (BCNU, GliadelTM wafers, CCNU, nimustine (ACNU), bendamustine (TreandaTM)); use with alkylating agents that damage DNA at a different place than does DAG (TMZ, BCNU, CCNU, and other alkylating agents all damage DNA at O 6 of guanine, whereas DAG cross-links at N 7 ); use with a monofunctional alkylating agent; use with a bifunctional alkylating agent; use with anti-tubulin agents; use with anti
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by exploiting the substituted hexitol derivative such as dianhydrogalactitol as a chemosensitizer where no measurable activity is observed when used alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • the substituted hexitol derivative such as dianhydrogalactitol as a chemosensitizer
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: as a chemosensitizer in combination with topoisomerase inhibitors; as a chemosensitizer in combination with fraudulent nucleosides; as a chemosensitizer in combination with fraudulent nucleotides; as a chemosensitizer in combination with thymidylate synthetase inhibitors; as a chemosensitizer in combination with signal transduction inhibitors; as a chemosensitizer in combination with cisplatin or platinum analogs; as a chemosensitizer in combination with alkylating agents such as BCNU, BCNU wafers, GliadelTM, CCNU, bendamustine (TreandaTM), or Temozolomide (TemodarTM); as a chemosensitizer in combination with anti-tubulin agents; as a chemosen
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by exploiting the substituted hexitol derivative such as dianhydrogalactitol as a chemopotentiator where minimal therapeutic activity is observed alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • the substituted hexitol derivative such as dianhydrogalactitol as a chemopotentiator
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: as a chemopotentiator in combination with topoisomerase inhibitors; as a chemopotentiator in combination with fraudulent nucleosides; as a chemopotentiator in combination with thymidylate synthetase inhibitors; as a chemopotentiator in combination with signal transduction inhibitors; as a chemopotentiator in combination with cisplatin or platinum analogs; as a chemopotentiator in combination with use with alkylating agents such as BCNU, BCNU wafers, GliadelTM, or bendamustine (TreandaTM); as a chemopotentiator in combination with anti-tubulin agents; as a chemopotentiator in combination with antimetabolites; as a chemopotentiator in combination with berberine; as a
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by drugs, treatments and diagnostics to allow for the maximum benefit to patients treated with a compound.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: pain management, nutritional support, anti-emetics, anti-nausea therapies, anti-anemia therapy, anti-inflammatories.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use with therapies associated with pain management; nutritional support; anti-emetics; anti-nausea therapies; anti-anemia therapy; anti-inflammatories: antipyretics; immune stimulants.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by the use of complementary therapeutics or methods to enhance effectiveness or reduce side effects.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: hypnosis; acupuncture; meditation; herbal medications created either synthetically or through extraction including NF- ⁇ B inhibitors (such as parthenolide, curcumin, rosmarinic acid); natural anti-inflammatories (including rhein, parthenolide); immunostimulants (such as those found in Echinacea ); antimicrobials (such as berberine); flavonoids, isoflavones, and flavones (such as apigenenin,
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the pharmaceutical bulk substance.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the pharmaceutical bulk substance.
  • General examples include: salt formation, homogeneous crystalline structure, pure isomers.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: salt formation; homogeneous crystalline structure; pure isomers; increased purity; lower residual solvents; or lower heavy metals.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the diluents used to solubilize and deliver/present the compound for administration.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: Cremophor-ELTM, cyclodextrins for poorly water soluble compounds.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use of emulsions; dimethyl sulfoxide (DMSO); N-methylformamide (NMF); dimethylformamide (DMF); dimethylacetamide (DMA); ethanol; benzyl alcohol; dextrose containing water for injection; CremophorTM; cyclodextrins; PEG.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the solvents used or required to solubilize a compound for administration or for further dilution.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: ethanol, dimethylacetamide (DMA).
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of emulsions; DMSO; NMF; DMF; DMA; ethanol; benzyl alcohol; dextrose containing water for injection; CremophorTM; cyclodextrin; or PEG.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the materials/excipients, buffering agents, or preservatives required to stabilize and present a chemical compound for proper administration.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of mannitol; albumin; EDTA; sodium bisulfite; benzyl alcohol; carbonate buffers; phosphate buffers.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the potential dosage forms of the compound dependent on the route of administration, duration of effect, plasma levels required, exposure to side effects in normal tissues and metabolizing enzymes.
  • General examples include: tablets, capsules, topical gels, creams, patches, suppositories.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of tablets; capsules; topical gels; topical creams; patches; suppositories; lyophilized dosage fills.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations in the dosage forms, container/closure systems, accuracy of mixing and dosage preparation and presentation.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: amber vials to protect from light, stoppers with specialized coatings.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of amber vials to protect from light; stoppers with specialized coatings to improve shelf-life stability.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by the use of delivery systems to improve the potential attributes of a pharmaceutical product such as convenience, duration of effect, reduction of toxicities.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: nanocrystals, bioerodible polymers, liposomes, slow release injectable gels, microspheres.
  • Specific inventive examples for a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of nanocrystals; bioerodible polymers; liposomes; slow release injectable gels; microspheres.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations to the parent molecule with covalent, ionic, or hydrogen bonded moieties to alter the efficacy, toxicity, pharmacokinetics, metabolism, or route of administration.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • covalent, ionic, or hydrogen bonded moieties to alter the efficacy, toxicity, pharmacokinetics, metabolism, or route of administration.
  • General examples include: polymer systems such as polyethylene glycols, polylactides, polyglycolides, amino acids, peptides, or multivalent linkers.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of polymer systems such as polyethylene glycols; polylactides; polyglycolides; amino acids; peptides; multivalent linkers.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by alterations to the molecule such that improved pharmaceutical performance is gained with a variant of the active molecule in that after introduction into the body a portion of the molecule is cleaved to reveal the preferred active molecule.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of enzyme sensitive esters; dimers; Schiff bases; pyridoxal complexes; caffeine complexes.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by the use of additional compounds, biological agents that, when administered in the proper fashion, a unique and beneficial effect can be realized.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • additional compounds biological agents that, when administered in the proper fashion, a unique and beneficial effect can be realized.
  • General examples include: inhibitors of multi-drug resistance, specific drug resistance inhibitors, specific inhibitors of selective enzymes, signal transduction inhibitors, repair inhibition.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use of inhibitors of multi-drug resistance; specific drug resistance inhibitors; specific inhibitors of selective enzymes; signal transduction inhibitors; repair inhibition; topoisomerase inhibitors with non-overlapping side effects.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by the use of the substituted hexitol derivative such as dianhydrogalactitol in combination as sensitizers/potentiators with biological response modifiers.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: use in combination as sensitizers/potentiators with biological response modifiers, cytokines, lymphokines, therapeutic antibodies, antisense therapies, gene therapies.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use in combination as sensitizers/potentiators with biological response modifiers; cytokines; lymphokines; therapeutic antibodies such as AvastinTM, HerceptinTM, RituxanTM, and ErbituxTM; antisense therapies; gene therapies; ribozymes; RNA interference; or vaccines.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by exploiting the selective use of the substituted hexitol derivative such as dianhydrogalactitol to overcome developing or complete resistance to the efficient use of biotherapeutics.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: tumors resistant to the effects of biological response modifiers, cytokines, lymphokines, therapeutic antibodies, antisense therapies, gene therapies.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use against tumors resistant to the effects of biological response modifiers; cytokines; lymphokines; therapeutic antibodies; antisense therapies; therapies such as AvastinTM, RituxanTM, HerceptinTM, ErbituxTM; gene therapies; ribozymes; RNA interference; and vaccines.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by exploiting their use in combination with ionizing radiation, phototherapies, heat therapies, or radio-frequency generated therapies.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • General examples include: hypoxic cell sensitizers, radiation sensitizers/protectors, photosensitizers, radiation repair inhibitors.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use in combination with ionizing radiation; use in combination with hypoxic cell sensitizers; use in combination with radiation sensitizers/protectors; use in combination with photosensitizers; use in combination with radiation repair inhibitors; use in combination with thiol depletion; use in combination with vaso-targeted agents; use in combination with use with radioactive seeds; use in combination with radionuclides; use in combination with radiolabeled antibodies; use in combination with brachytherapy.
  • Radiotherapy can be used for treatment of non-small-cell lung carcinoma (NSCLC), either alone or together with chemotherapy.
  • NSCLC non-small-cell lung carcinoma
  • the use of radiotherapy for the treatment of NSCLC has been described in M. Provencio et al., “Inoperable Stage III Non-Small Cell Lung Cancer: Current Treatment and Role of Vinorelbine,” J. Thoracic Dis. 3:197-204 (2011), incorporated herein by this reference.
  • Various dosage protocols can be used, and radiation can be administered either concurrently or separately with chemotherapy when both radiation and chemotherapy are used.
  • Radiation can be administered in either a single dose, or in fractionated doses. A typical single dose is 60 Gy, but when radiation is administered in fractionated doses, a somewhat higher dosage can be administered in toto.
  • Total doses can range from about 40 Gy to about 79.2 Gy.
  • Radiation can be administered as high-energy X-rays or high-energy electrons from linear accelerator units; in some cases, gamma rays can be administered from a cobalt-60-based device.
  • Other radiotherapy methods are known in the art.
  • radiotherapy is also frequently used; the use of radiotherapy for the treatment of GBM is described in T. N. Showalter et al., “Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression,” Int. J. Radiation Oncol. Biol. Phys. 69:820-824 (2007), incorporated herein by this reference.
  • a dose of about 60 Gy is generally considered optimal, and three-dimensional conformal radiotherapy is frequently used.
  • GBM tumors frequently include regions with hypoxia that are resistant to radiotherapy, in one alternative, a radiosensitizer such as trans sodium crocetinate can be used.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by optimizing its utility by determining the various mechanisms of action, biological targets of a compound for greater understanding and precision to better exploit the utility of the molecule.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: the use with inhibitors of poly-ADP ribose polymerase; agents that effect vasculature or vasodilation; oncogenic targeted agents; signal transduction inhibitors; EGFR inhibition; Protein Kinase C inhibition; Phospholipase C downregulation; Jun downregulation; histone genes; VEGF; ornithine decarboxylase; ubiquitin C; jun D; v-jun; GPCRs; protein kinase A; telomerase, prostate specific genes; protein kinases other than protein kinase A; histone deacetylase; and tyrosine kinase inhibitors.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by more precise identification and exposure of the compound to those select cell populations where the compound's effect can be maximally exploited, particularly NSCLC tumor cells or GBM tumor cells.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM include: use against radiation sensitive cells; use against radiation resistant cells; or use against energy depleted cells.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM made by use of an agent that counteracts myelosuppression.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC made by use of an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC
  • an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier can also be employed for GBM, which is a central nervous system malignancy.
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC or for GBM
  • chimeric peptides include chimeric peptides; compositions comprising either avidin or an avidin fusion protein bonded to a biotinylated substituted hexitol derivative; neutral liposomes that are pegylated and that incorporate the substituted hexitol derivative and wherein the polyethylene glycol strands are conjugated to at least one transportable peptide or targeting agent; a humanized murine antibody that binds to the human insulin receptor linked to the substituted hexitol derivative through an avidin-biotin linkage; and a fusion protein linked to the hexitol through an avidin-biotin linkage.
  • Yet another aspect of the invention is an improvement in the therapeutic employment of a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC or GBM made by use of an agent that suppresses the growth of cancer stem cells (CSCs).
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC or GBM
  • CSCs cancer stem cells
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC or for GBM
  • a substituted hexitol derivative such as dianhydrogalactitol for treatment of brain metastases of NSCLC or for GBM
  • one aspect of the present invention is a method to improve the efficacy and/or reduce the side effects of the administration of a substituted hexitol derivative such as dianhydrogalactitol for treatment of NSCLC or GBM comprising the steps of:
  • the factor or parameter is selected from the group consisting of:
  • CSC cancer stem cells
  • the substituted hexitol derivative usable in methods and compositions according to the present invention include galactitols, substituted galacitols, dulcitols, and substituted dulcitols, including dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, and derivatives and analogs thereof.
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the substituted hexitol derivative is dianhydrogalactitol.
  • the dose modification can be, but is not limited to, at least one dose modification selected from the group consisting of:
  • the route of administration can be, but is not limited to, at least one route of administration selected from the group consisting of:
  • the schedule of administration can be, but is not limited to, at least one schedule of administration selected from the group consisting of:
  • the selection of disease stage can be, but is not limited to, at least one selection of disease stage selected from the group consisting of:
  • the patient selection can be, but is not limited to, a patient selection carried out by a criterion selected from the group consisting of:
  • the cellular proto-oncogene c-Jun encodes a protein that, in combination with c-Fos, forms the AP-1 early response transcription factor.
  • This proto-oncogene plays a key role in transcription and interacts with a large number of proteins affecting transcription and gene expression. It is also involved in proliferation and apoptosis of cells that form part of a number of tissues, including cells of the endometrium and glandular epithelial cells.
  • G-protein coupled receptors GPCRs
  • the superfamily of G protein coupled receptors includes a large number of receptors. These receptors are integral membrane proteins characterized by amino acid sequences that contain seven hydrophobic domains, predicted to represent the transmembrane spanning regions of the proteins.
  • GPCR receptors include, but are not limited to, acetylcholine receptors, ⁇ -adrenergic receptors, ⁇ 3 -adrenergic receptors, serotonin (5-hydroxytryptamine) receptors, dopamine receptors, adenosine receptors, angiotensin Type II receptors, bradykinin receptors, calcitonin receptors, calcitonin gene-related receptors, cannabinoid receptors, cholecystokinin receptors, chemokine receptors, cytokine receptors, gastrin receptors, endothelin receptors, ⁇ -aminobutyric acid (GABA) receptors, galanin receptors, glucagon receptors, glutamate receptors, luteinizing hormone receptors, choriogonadotrophin receptors, follicle-stimulating hormone receptors, thyroid-stimulating hormone receptors, gonadotrophin-releasing hormone receptors, leukotriene receptors
  • EGFR mutations can be associated with sensitivity to therapeutic agents such as gefitinib, as described in J. G. Paez et al., “EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib,” Science 304:1497-1500 (2004), incorporated herein by this reference.
  • One specific mutation in EGFR that is associated with resistance to tyrosine kinase inhibitors is known as EGFR Variant III, which is described in C. A. Learn et al., “Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme,” Clin. Cancer Res.
  • EGFR Variant III is characterized by a consistent and tumor-specific in-frame deletion of 801 bp from the extracellular domain that splits a codon and produces a novel glycine at the fusion junction.
  • This mutation encodes a protein with a constituently active thymidine kinase that enhances the tumorigenicity of the cells carrying this mutation. This mutated protein sequence is absent from normal tissues.
  • these polymorphisms include, but are not necessarily limited to, polymorphisms in the gene BCL2L11 (also known as BIM), which encodes a BH3-only protein that is a BCL-2 family member.
  • BCL2L11 also known as BIM
  • BCL2L1 BCL2-like 1
  • MCL1 myeloid cell leukemia sequence 1
  • BCL2A1 BCL2-related protein A1
  • BAX pro-apoptotic BCL2 family members
  • BAK1 BCL2-associated X protein
  • BAK1 BCL2-antagonist/killer 1
  • kinase-driven cancers such as CML and EGFR NSCLC
  • can maintain a survival advantage by suppressing BIM transcription and also by targeting BIM protein for proteasomal degradation through mitogen-activated protein kinase 1 (MAPK-1)-dependent phosphorylation.
  • MAPK-1 mitogen-activated protein kinase 1
  • the presence of the polymorphism was correlated with a lesser degree of response to imatinib, a TKI, in CML, as well as a shorter progression-free survival (PFS) with EGFR TKI therapy in EGFR NSCLC (K. P. Ng et al., “A Common BIM Deletion Polymorphism Mediates Intrinsic Resistance and Inferior Responses to Tyrosine Kinase Inhibitors in Cancer,” Nature Med . doi 10.138/nm.2713 (Mar. 18, 2012), incorporated herein by this reference).
  • the analysis of patient or disease phenotype can be, but is not limited to, a method of analysis of patient or disease phenotype carried out by a method selected from the group consisting of:
  • the analysis of patient or disease genotype can be, but is not limited to, a method of analysis of patient or disease genotype carried out by a method selected from the group consisting of:
  • the SNP analysis can be carried out on a gene selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, a prostate specific gene, c-Jun, and a protein kinase.
  • SNP analysis is described in S. Levy and Y.-H. Rogers, “DNA Sequencing for the Detection of Human Genome Variation” in Essentials of Genomic and Personalized Medicine (G. S. Ginsburg & H. F. Willard, eds., Academic Press, Amsterdam, 2010), ch. 3, pp. 27-37, incorporated herein by this reference.
  • the pre/post-treatment preparation can be, but is not limited to, a method of pre/post treatment preparation selected from the group consisting of:
  • Uricosurics include, but are not limited to, probenecid, benzbromarone, and sulfinpyrazone. A particularly preferred uricosuric is probenecid. Uricosurics, including probenecid, may also have diuretic activity. Other diuretics are well known in the art, and include, but are not limited to, hydrochlorothiazide, carbonic anhydrase inhibitors, furosemide, ethacrynic acid, amiloride, and spironolactone.
  • Poly-ADP ribose polymerase inhibitors are described in G. J. Southan & C. Szabó, “Poly(ADP-Ribose) Inhibitors,” Curr. Med. Chem. 10:321-240 (2003), incorporated herein by this reference, and include nicotinamide, 3-aminobenzamide, substituted 3,4-dihydroisoquinolin-1(2H)-ones and isoquinolin-1(2H)-ones, benzimidazoles, indoles, phthalazin-1(2H)-ones, quinazolinones, isoindolinones, phenanthridinones, and other compounds.
  • Leucovorin rescue comprises administration of folinic acid (leucovorin) to patients in which methotrexate has been administered.
  • Leucovorin is a reduced form of folic acid that bypasses dihydrofolate reductase and restores hematopoietic function.
  • Leucovorin can be administered either intravenously or orally.
  • the uricosuric is probenecid or an analog thereof.
  • the toxicity management can be, but is not limited to, a method of toxicity management selected from the group consisting of:
  • Filgrastim is a granulocytic colony-stimulating factor (G-CSF) analog produced by recombinant DNA technology that is used to stimulate the proliferation and differentiation of granulocytes and is used to treat neutropenia; G-CSF can be used in a similar manner.
  • G-CSF is granulocyte macrophage colony-stimulating factor and stimulates stem cells to produce granulocytes (eosinophils, neutrophils, and basophils) and monocytes; its administration is useful to prevent or treat infection.
  • Anti-inflammatory agents are well known in the art and include corticosteroids and non-steroidal anti-inflammatory agents (NSAIDs).
  • Corticosteroids with anti-inflammatory activity include, but are not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide, and fludrocortisone.
  • Non-steroidal anti-inflammatory agents include, but are not limited to, acetylsalicylic acid (aspirin), sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofin, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, nimesulide, aceclofenac, alclofenac, alminoprofen, amfenac, ampiroxicam, apazone, araprofen, azapropazone
  • corticosteroids The clinical use of corticosteroids is described in B. P. Schimmer & K. L. Parker, “Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones” in Goodman & Gilman's The Pharmacological Basis of Therapeutics (L. L. Brunton, ed., 11 th ed., McGraw-Hill, New York, 2006), ch. 59, pp. 1587-1612, incorporated herein by this reference.
  • Anti-nausea treatments include, but are not limited to, ondansetron, metoclopramide, promethazine, cyclizine, hyoscine, dronabinol, dimenhydrinate, diphenhydramine, hydroxyzine, ismethosetron, domperidone, haloperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, betamethasone, dexamethasone, lorazepam, and thiethylperazine.
  • Anti-diarrheal treatments include, but are not limited to, diphenoxylate, difenoxin, loperamide, codeine, racecadotril, octreoside, and berberine.
  • N-acetylcysteine is an antioxidant and mucolytic that also provides biologically accessible sulfur.
  • Poly-ADP ribose polymerase (PARP) inhibitors include, but are not limited to: (1) derivatives of tetracycline as described in U.S. Pat. No. 8,338,477 to Duncan et al.; (2) 3,4-dihydro-5-methyl-1(2H)-isoquinoline, 3-aminobenzamide, 6-aminonicotinamide, and 8-hydroxy-2-methyl-4(3H)-quinazolinone, as described in U.S. Pat. No. 8,324,282 by Gerson et al.; (3) 6-(5H)-phenanthridinone and 1,5-isoquinolinediol, as described in U.S. Pat. No.
  • PARP Poly-ADP ribose polymerase
  • the pharmacokinetic/pharmacodynamic monitoring can be, but is not limited to a method selected from the group consisting of:
  • immunoassays typically include radioimmunoassay, ELISA (enzyme-linked immunosorbent assay), competitive immunoassay, immunoassay employing lateral flow test strips, and other assay methods.
  • the drug combination can be, but is not limited to, a drug combination selected from the group consisting of:
  • Topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, camptothecin, lamellarin D, amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, and ICRF-193.
  • Fraudulent nucleosides include, but are not limited to, cytosine arabinoside, gemcitabine, and fludarabine; other fraudulent nucleosides are known in the art.
  • Fraudulent nucleotides include, but are not limited to, tenofovir disoproxil fumarate and adefovir dipivoxil; other fraudulent nucleotides are known in the art.
  • Thymidylate synthetase inhibitors include, but are not limited to, raltitrexed, pemetrexed, nolatrexed, ZD9331, GS7094L, fluorouracil, and BGC 945.
  • Alkylating agents include, but are not limited to, Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bendamustine, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine (BCNU), Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr) 2 , diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoi
  • Temozolomide, BCNU, CCNU, and ACNU all damage DNA at O 6 of guanine, whereas DAG cross-links at N 7 ); one alternative is therefore to use DAG in combination with an alkylating agent that damages DNA at a different place than DAG.
  • the alkylating agent can be a monofunctional alkylating agent or a bifunctional alkylating agent.
  • Monofunctional alkylating agents include, but are not limited to, carmustine lomustine, temozolomide, and dacarbazine, as described in N. Kondo et al., “DNA Damage Induced by Alkylating Agents and Repair Pathways,” J.
  • monofunctional alkylating agents also include such agents as methyl methanesulfonate, ethylmethanesulfonate, and N-methyl-N-nitrosoguanidine, as described in J. M. Walling & I. J. Stratford, “Chemosensitization by Monofunctional Alkylating Agents,” Int. J. Radiat. Oncol. Biol. Phys. 12:1397-1400 (1986), incorporated herein by this reference.
  • Bifunctional alkylating agents include, but are not limited to, mechlorethamine, chlorambucil, cyclophosphamide, busulfan, nimustine, carmustine, lomustine, fotemustine, and bis-(2-chloroethyl) sulfide (N. Kondo et al. (2010), supra).
  • One significant class of bifunctional alkylating agents includes alkylating agents that target O 6 of guanine in DNA.
  • alkylating agents comprises cisplatin and other platinum-containing agents, including, but not limited to, carboplatin, iproplatin, oxaliplatin, tetraplatin, satraplatin, picoplatin, nedaplatin, and triplatin. These agents cause cross-linking of DNA, which then induces apoptosis.
  • the combination with cisplatin or other platinum-containing agents is a potential component of standard platinum doublet therapy.
  • the ability to be more than additive or synergistic is particularly significant with respect to the combination of a substituted hexitol derivative such as dianhydrogalactitol with cisplatin or other platinum-containing chemotherapeutic agents, as well as other chemotherapeutic agents recited herein.
  • Anti-tubulin agents include, but are not limited to, vinca alkaloids, taxanes, podophyllotoxin, halichondrin B, and homohalichondrin B.
  • Antimetabolites include, but are not limited to: methotrexate, pemetrexed, 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, and pentostatin, alanosine, AG2037 (Pfizer), 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrill-Dow DDFC, deazaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co.
  • EX-015 benzrabine, floxuridine, fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricytin.
  • Berberine has antibiotic activity and prevents and suppresses the expression of pro-inflammatory cytokines and E-selectin, as well as increasing adiponectin expression.
  • Apigenin is a flavone that can reverse the adverse effects of cyclosporine and has chemoprotective activity, either alone or derivatized with a sugar.
  • Amonafide is a topoisomerase inhibitor and DNA intercalator that has anti-neoplastic activity.
  • Curcumin is believed to have anti-neoplastic, anti-inflammatory, antioxidant, anti-ischemic, anti-arthritic, and anti-amyloid properties and also has hepatoprotective activity.
  • NF- ⁇ B inhibitors include, but are not limited to, bortezomib.
  • Rosmarinic acid is a naturally-occurring phenolic antioxidant that also has anti-inflammatory activity.
  • Mitoguazone is an inhibitor of polyamine biosynthesis through competitive inhibition of S-adenosylmethionine decarboxylase.
  • Tetrandrine has the chemical structure 6,6′,7,12-tetramethoxy-2,2′-dimethyl-1 ⁇ -berbaman and is a calcium channel blocker that has anti-inflammatory, immunologic, and antiallergenic effects, as well as an anti-arrhythmic effect similar to that of quinidine. It has been isolated from Stephania tetranda and other Asian herbs.
  • VEGF inhibitors include bevacizumab (AvastinTM), which is a monoclonal antibody against VEGF, itraconazole, and suramin, as well as batimastat and marimastat, which are matrix metalloproteinase inhibitors, and cannabinoids and derivatives thereof.
  • vastinTM a monoclonal antibody against VEGF
  • itraconazole and suramin
  • batimastat and marimastat which are matrix metalloproteinase inhibitors, and cannabinoids and derivatives thereof.
  • Cancer vaccines are being developed. Typically, cancer vaccines are based on an immune response to a protein or proteins occurring in cancer cells that does not occur in normal cells. Cancer vaccines include ProvengeTM for metastatic hormone-refractory prostate cancer, OncophageTM for kidney cancer, CimaVax-EGFTM for lung cancer, MOBILAN, Neuvenge for Her2/neu expressing cancers such as breast cancer, colon cancer, bladder cancer, and ovarian cancer, StimuvaxTM for breast cancer, and others. Cancer vaccines are described in S. Pejawar-Gaddy & O. Finn, “Cancer Vaccines: Accomplishments and Challenges,” Crit. Rev. Oncol. Hematol. 67:93-102 (2008), incorporated herein by this reference.
  • the epidermal growth factor receptor exists on the cell surface of mammalian cells and is activated by binding of the receptor to its specific ligands, including, but not limited to epidermal growth factor and transforming growth factor ⁇ .
  • EGFR Upon activation by binding to its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer, although preformed active dimers may exist before ligand binding.
  • EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer.
  • the signaling of these proteins that associate with the phosphorylated tyrosine residues through their own phosphotyrosine-binding SH2 domains can then initiate several signal transduction cascades and lead to DNA synthesis and cell proliferation.
  • the kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors that it is aggregated with, and can itself be activated in that manner.
  • EGFR is encoded by the c-erbB1 proto-oncogene and has a molecular mass of 170 kDa.
  • domains I and III which have 37% sequence identity, are cysteine-poor and conformationally contain the site for ligand (EGF and transforming growing factor ⁇ (TGF ⁇ ) binding.
  • Cysteine-rich domains II and IV contain N-linked glycosylation sites and disulfide bonds, which determine the tertiary conformation of the external domain of the protein molecule.
  • TGF ⁇ expression has a strong correlation with EGFR overexpression, and therefore TGF ⁇ was considered to act in an autocrine manner, stimulating proliferation of the cells in which it is produced via activation of EGFR.
  • Binding of a stimulatory ligand to the EGFR extracellular domain results in receptor dimerization and initiation of intracellular signal transduction, the first step of which is activation of the tyrosine kinase.
  • the earliest consequence of kinase activation is the phosphorylation of its own tyrosine residues (autophosphorylation) as described above. This is followed by association with activation of signal transducers leading to mitogenesis.
  • EGFR Variant III A specific mutation of EGFR known as EGFR Variant III has frequently been observed in glioblastoma (C. T. Kuan et al., “EGF Mutant Receptor VIII as a Molecular Target in Cancer Therapy,” Endocr. Relat. Cancer 8:83-96 (2001), incorporated herein by this reference). EGFR is considered an oncogene.
  • Inhibitors of EGFR include, but are not limited to, erlotinib, gefitinib, lapatinib, lapatinib ditosylate, afatinib, canertinib, neratinib, CP-724714, WHI-P154, TAK-285, AST-1306, ARRY-334543, ARRY-380, AG-1478, tyrphostin 9, dacomitinib, desmethylerlotinib, OSI-420, AZD8931, AEE788, pelitinib, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035 HCl, BMS-599626, BIBW 2992, CI 1033, CP 724714, OSI 420, and vandetinib.
  • Particularly preferred EGFR inhibitors include erlotinib, afatinib, and lapati
  • Tyrosine kinase inhibitors include, but are not limited to, imatinib, gefitinib, erlotinib, sunitinib, sorafenib, foretinib, cederinib, axitinib, carbozantinib, BIBF1120, golvatinib, dovitinib, ZM 306416, ZM 323881 HCl, SAR 131675, semaxinib, telatinib, pazopanib, ponatinib, crenolanib, tivanitib, mubritinib, danusertib, brivanib, fingolimod, saracatinib, rebastinib, quizartinib, tandutinib, amuvatinib, ibrutinib, fostamatinib, crizotinib, and linsitinib
  • Such tyrosine kinase inhibitors can inhibit tyrosine kinases associated with one or more of the following receptors: VEGFR, EGFR, PDGFR, c-Kit, c-Met, Her-2, FGFR, FLT-3, IGF-1R, ALK, c-RET, and Tie-2.
  • EGFR epidermal growth factor receptor
  • a number of tyrosine kinase inhibitors inhibit the activity of both EGFR and at least one other tyrosine kinase.
  • tyrosine kinase inhibitors can operate by four different mechanisms: competition with adenosine triphosphate (ATP), used by the tyrosine kinase to carry out the phosphorylation reaction; competition with the substrate; competition with both ATP and the substrate; or allosteric inhibition.
  • ATP adenosine triphosphate
  • the activity of these inhibitors is disclosed in P. Yaish et al., “Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors,” Science 242:933-935 (1988); A. Gazit et al., “Tyrphostins. 2.
  • ALK inhibitors act on tumors with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation.
  • ALK inhibitors include, but are not limited to: crizotinib (3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine); AP26113 ((2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide); ASP-3026 (N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-[2-[(1-methylethyl)sulfon
  • the chemosensitization can comprise, but is not limited to, the use of a substituted hexitol derivative as a chemosensitizer in combination with an agent selected from the group consisting of:
  • the chemopotentiation can comprise, but is not limited to, the use of a substituted hexitol derivative as a chemopotentiator in combination with an agent selected from the group consisting of:
  • the post-treatment management can be, but is not limited to, a method selected from the group consisting of:
  • the alternative medicine/post-treatment support can be, but is not limited to, a method selected from the group consisting of:
  • the method when the method is a herbal medication created either synthetically or through extraction, the herbal medication created either synthetically or through extraction can be selected from the group consisting of:
  • the NF- ⁇ B inhibitor can be selected from the group consisting of parthenolide, curcumin, and rosmarinic acid.
  • the natural anti-inflammatory can be selected from the group consisting of rhein and parthenolide.
  • the immunostimulant can be a product found in or isolated from Echinacea .
  • the anti-microbial can be berberine.
  • the flavonoid, isoflavone, or flavone can be selected from the group consisting of apigenin, genistein, apigenenin, genistein, genistin, 6′′-O-malonylgenistin, 6′′-O-acetylgenistin, daidzein, daidzin, 6′′-O-malonyldaidzin, 6′′-O-acetylgenistin, glycitein, glycitin, 6′′-O-malonylglycitin, and 6-O-acetylglycitin.
  • the bulk drug product improvement can be, but is not limited to, a bulk drug product improvement selected from the group consisting of:
  • the diluent can be, but is not limited to, a diluent selected from the group consisting of:
  • the solvent system can be, but is not limited to, a solvent system selected from the group consisting of:
  • the excipient can be, but is not limited to, an excipient selected from the group consisting of:
  • the dosage form can be, but is not limited to, a dosage form selected from the group consisting of:
  • Formulation of pharmaceutical compositions in tablets, capsules, and topical gels, topical creams or suppositories is well known in the art and is described, for example, in United States Patent Application Publication No. 2004/0023290 by Griffin et al., incorporated herein by this reference.
  • compositions as patches such as transdermal patches is well known in the art and is described, for example, in U.S. Pat. No. 7,728,042 to Eros et al., incorporated herein by this reference.
  • Lyophilized dosage fills are also well known in the art.
  • One general method for the preparation of such lyophilized dosage fills, applicable to dianhydrogalactitol and derivatives thereof and to diacetyldianhydrogalactitol and derivatives thereof, comprises the following steps:
  • Vacuum is then turned on, the shelf temperature is adjusted to ⁇ 5° C., and primary drying is performed for 8 hours; the shelf temperature is again adjusted to ⁇ 5° C. and drying is carried out for at least 5 hours.
  • Secondary drying is started after the condenser (set at ⁇ 60° C.) and vacuum are turned on.
  • the shelf temperature is controlled at +5° C. for 1 to 3 hours, typically 1.5 hours, then at 25° C. for 1 to 3 hours, typically 1.5 hours, and finally at 35-40° C. for at least 5 hours, typically for 9 hours, or until the product is completely dried.
  • Vials are removed from the lyophilizer chamber and sealed with aluminum flip-off seals. All vials are visually inspected and labeled with approved labels.
  • the dosage kits and packaging can be, but are not limited to, dosage kits and packaging selected from the group consisting of the use of amber vials to protect from light and the use of stoppers with specialized coatings to improve shelf-life stability.
  • the dosage kits can be labeled to indicate details of use and may contain one or more than one therapeutically active agent; if more than one therapeutic agent is included, the two or more therapeutic agents can be combined or separately packaged.
  • the drug delivery system can be, but is not limited to, a drug delivery system selected from the group consisting of:
  • Nanocrystals are described in U.S. Pat. No. 7,101,576 to Hovey et al., incorporated herein by this reference.
  • Bioerodible polymers are described in U.S. Pat. No. 7,318,931 to Okumu et al., incorporated herein by this reference.
  • a bioerodible polymer decomposes when placed inside an organism, as measured by a decline in the molecular weight of the polymer over time.
  • Polymer molecular weights can be determined by a variety of methods including size exclusion chromatography (SEC), and are generally expressed as weight averages or number averages.
  • SEC size exclusion chromatography
  • a polymer is bioerodible if, when in phosphate buffered saline (PBS) of pH 7.4 and a temperature of 37° C., its weight-average molecular weight is reduced by at least 25% over a period of 6 months as measured by SEC.
  • PBS phosphate buffered saline
  • Useful bioerodible polymers include polyesters, such as poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(hydroxybutyrate); polyanhydrides, such as poly(adipic anhydride) and poly(maleic anhydride); polydioxanone; polyamines; polyamides; polyurethanes; polyesteramides; polyorthoesters; polyacetals; polyketals; polycarbonates; polyorthocarbonates; polyphosphazenes; poly(malic acid); poly(amino acids); polyvinylpyrrolidone; poly(methyl vinyl ether); poly(alkylene oxalate); poly(alkylene succinate); polyhydroxycellulose; chitin; chitosan; and copolymers and mixtures thereof.
  • polyesters such as poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(hydroxybutyrate
  • polyanhydrides such as poly(adipic anhydride) and poly
  • Liposomes are well known as drug delivery vehicles. Liposome preparation is described in European Patent Application Publication No. EP 1332755 by Weng et al., incorporated herein by this reference.
  • microspheres for drug delivery is known in the art and is described, for example, in H. Okada & H. Taguchi, “Biodegradable Microspheres in Drug Delivery,” Crit. Rev. Ther. Drug Carrier Sys. 12:1-99 (1995), incorporated herein by this reference.
  • the drug conjugate form can be, but is not limited to, a drug conjugate form selected from the group consisting of:
  • Polylactide conjugates are well known in the art and are described, for example, in R. Tong & C. Cheng, “Controlled Synthesis of Camptothecin-Polylactide Conjugates and Nanoconjugates,” Bioconjugate Chem. 21:111-121 (2010), incorporated by this reference.
  • Polyglycolide conjugates are also well known in the art and are described, for example, in PCT Patent Application Publication No. WO 2003/070823 by Elmaleh et al., incorporated herein by this reference.
  • Multivalent linkers are known in the art and are described, for example, in United States Patent Application Publication No. 2007/0207952 by Silva et al., incorporated herein by this reference.
  • multivalent linkers can contain a thiophilic group for reaction with a reactive cysteine, and multiple nucleophilic groups (such as NH or OH) or electrophilic groups (such as activated esters) that permit attachment of a plurality of biologically active moieties to the linker.
  • electrophilic groups can react with many functional groups, including those present in proteins or polypeptides.
  • Various combinations of reactive amino acids and electrophiles are known in the art and can be used.
  • N-terminal cysteines, containing thiol groups can be reacted with halogens or maleimides.
  • Thiol groups are known to have reactivity with a large number of coupling agents, such as alkyl halides, haloacetyl derivatives, maleimides, aziridines, acryloyl derivatives, arylating agents such as aryl halides, and others. These are described in G. T.
  • the reactivity of the cysteine residues can be optimized by appropriate selection of the neighboring amino acid residues. For example, a histidine residue adjacent to the cysteine residue will increase the reactivity of the cysteine residue.
  • Other combinations of reactive amino acids and electrophilic reagents are known in the art.
  • maleimides can react with amino groups, such as the ⁇ -amino group of the side chain of lysine, particularly at higher pH ranges.
  • Aryl halides can also react with such amino groups.
  • Haloacetyl derivatives can react with the imidazolyl side chain nitrogens of histidine, the thioether group of the side chain of methionine, and the ⁇ -amino group of the side chain of lysine.
  • Many other electrophilic reagents are known that will react with the ⁇ -amino group of the side chain of lysine, including, but not limited to, isothiocyanates, isocyanates, acyl azides, N-hydroxysuccinimide esters, sulfonyl chlorides, epoxides, oxiranes, carbonates, imidoesters, carbodiimides, and anhydrides. These are described in G. T.
  • electrophilic reagents are known that will react with hydroxyl groups such as those in the side chains of serine and threonine, including reactive haloalkane derivatives. These are described in G. T. Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996), pp. 154-158, incorporated herein by this reference.
  • the relative positions of electrophile and nucleophile i.e., a molecule reactive with an electrophile
  • the relative positions of electrophile and nucleophile are reversed so that the protein has an amino acid residue with an electrophilic group that is reactive with a nucleophile and the targeting molecule includes therein a nucleophilic group.
  • amino groups can be reacted with isothiocyanates, isocyanates, acyl azides, N-hydroxysuccinimide (NHS) esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, alkylating agents, imidoesters, carbodiimides, and anhydrides.
  • isothiocyanates isocyanates
  • acyl azides N-hydroxysuccinimide (NHS) esters
  • sulfonyl chlorides aldehydes, glyoxals, epoxides, oxiranes
  • alkylating agents imidoesters, carbodiimides, and anhydrides.
  • Thiol groups can be reacted with haloacetyl or alkyl halide derivatives, maleimides, aziridines, acryloyl derivatives, acylating agents, or other thiol groups by way of oxidation and the formation of mixed disulfides.
  • Carboxy groups can be reacted with diazoalkanes, diazoacetyl compounds, carbonyldiimidazole, carbodiimides.
  • Hydroxyl groups can be reacted with epoxides, oxiranes, carbonyldiimidazole, N,N′-disuccinimidyl carbonate, N-hydroxysuccinimidyl chloroformate, periodate (for oxidation), alkyl halogens, or isocyanates.
  • Aldehyde and ketone groups can react with hydrazines, reagents forming Schiff bases, and other groups in reductive amination reactions or Mannich condensation reactions. Still other reactions suitable for cross-linking reactions are known in the art. Such cross-linking reagents and reactions are described in G. T. Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996), incorporated herein by this reference.
  • the compound analog can be, but is not limited to, a compound analog selected from the group consisting of:
  • the prodrug system can be, but is not limited to, a prodrug system selected from the group consisting of:
  • prodrug systems are described in T. Järvinen et al., “Design and Pharmaceutical Applications of Prodrugs” in Drug Discovery Handbook (S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., 2005), ch. 17, pp. 733-796, incorporated herein by this reference.
  • This publication describes the use of enzyme sensitive esters as prodrugs.
  • dimers as prodrugs is described in U.S. Pat. No. 7,879,896 to Allegretti et al., incorporated herein by this reference.
  • the use of peptides in prodrugs is described in S.
  • the multiple drug system can be, but is not limited to, a multiple drug system selected from the group consisting of:
  • Multi-drug resistance inhibitors are described in U.S. Pat. No. 6,011,069 to Inomata et al., incorporated herein by this reference.
  • biotherapeutic enhancement can be performed by use in combination as sensitizers/potentiators with a therapeutic agent or technique that can be, but is not limited to, a therapeutic agent or technique selected from the group consisting of:
  • Antisense therapies are described, for example, in B. Weiss et al., “Antisense RNA Gene Therapy for Studying and Modulating Biological Processes,” Cell. Mol. Life Sci. 55:334-358 (1999), incorporated herein by this reference.
  • Ribozymes are described, for example, in S. Pascolo, “RNA-Based Therapies” in Drug Discovery Handbook (S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., 2005), ch. 27, pp. 1273-1278, incorporated herein by this reference.
  • RNA interference is described, for example, in S. Pascolo, “RNA-Based Therapies” in Drug Discovery Handbook (S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., 2005), ch. 27, pp. 1278-1283, incorporated herein by this reference.
  • cancer vaccines are based on an immune response to a protein or proteins occurring in cancer cells that does not occur in normal cells.
  • Cancer vaccines include ProvengeTM for metastatic hormone-refractory prostate cancer, OncophageTM for kidney cancer, CimaVax-EGFTM for lung cancer, MOBILAN, Neuvenge for Her2/neu expressing cancers such as breast cancer, colon cancer, bladder cancer, and ovarian cancer, StimuvaxTM for breast cancer, and others. Cancer vaccines are described in S. Pejawar-Gaddy & O. Finn, (2008), supra.
  • the therapeutic antibody can be, but is not limited to, a therapeutic antibody selected from the group consisting of bevacizumab (AvastinTM), rituximab (RituxanTM), trastuzumab (HerceptinTM), and cetuximab (ErbituxTM).
  • the biotherapeutic resistance modulation can be, but is not limited to, use against NSCLC or GBM resistant to a therapeutic agent or technique selected from the group consisting of:
  • the therapeutic antibody can be, but is not limited to, a therapeutic antibody selected from the group consisting of bevacizumab (AvastinTM), rituximab (RituxanTM), trastuzumab (HerceptinTM), and cetuximab (ErbituxTM).
  • the radiation therapy enhancement can be, but is not limited to, a radiation therapy enhancement agent or technique selected from the group consisting of:
  • a substituted hexitol derivative such as dianhydrogalactitol can be used in combination with radiation for the treatment of NSCLC, as described above.
  • hypoxic cell sensitizers are described in C. C. Ling et al., “The Effect of Hypoxic Cell Sensitizers at Different Irradiation Dose Rates,” Radiation Res. 109:396-406 (1987), incorporated herein by this reference. Radiation sensitizers are described in T. S. Lawrence, “Radiation Sensitizers and Targeted Therapies,” Oncology 17 (Suppl. 13):23-28 (2003), incorporated herein by this reference. Radiation protectors are described in S. B. Vuyyuri et al., “Evaluation of D-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis,” Clin. Cancer Res.
  • Vaso-targeted agents are described in A. L. Seynhaeve et al., “Tumor Necrosis Factor ⁇ Mediates Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response,” Cancer Res. 67:9455-9462 (2007).
  • radiation therapy is employed for the treatment of NSCLC, so radiation therapy enhancement is significant for this malignancy.
  • radiation therapy enhancement is significant for the treatment of GBM, as radiation therapy is frequently employed for this malignancy; hypoxic cell sensitizers are frequently employed for the treatment of GBM.
  • the novel mechanism of action can be, but is not limited to, a novel mechanism of action that is a therapeutic interaction with a target or mechanism selected from the group consisting of:
  • EGFR inhibition is described in G. Giaccone & J. A. Rodriguez, “EGFR Inhibitors: What Have We Learned from the Treatment of Lung Cancer,” Nat. Clin. Pract. Oncol. 11:554-561 (2005), incorporated herein by this reference.
  • Protein kinase C inhibition is described in H. C. Swannie & S. B. Kaye, “Protein Kinase C Inhibitors,” Curr. Oncol. Rep. 4:37-46 (2002), incorporated herein by this reference.
  • Phospholipase C downregulation is described in A. M.
  • selective target cell population therapeutics can be, but is not limited to, a use selected from the group consisting of:
  • the improvement can also be made by use of a substituted hexitol derivative in combination with ionizing radiation as described above, particularly with respect to the use of ionizing radiation for the treatment of NSCLC or GBM as described above.
  • the agent that counteracts myelosuppression can be, but is not limited to, a dithiocarbamate.
  • U.S. Pat. No. 5,035,878 to Borch et al. discloses dithiocarbamates for treatment of myelosuppression; the dithiocarbamates are compounds of the formula R 1 R 2 NCS(S)M or R 1 R 2 NCSS—SC(S)NR 3 R 4 , wherein R 1 , R 2 , R 3 , and R 4 are the same or different, and R 1 , R 2 , R 3 , and R 4 are aliphatic, cycloaliphatic, or heterocycloaliphatic groups that are unsubstituted or substituted by hydroxyl; or wherein one of R 1 and R 2 and one of R 3 and R 4 can be hydrogen; or wherein R 1 , R 2 , R 3 , and R 4 taken together with the nitrogen atom upon which the pair of R groups is substituted, can be a 5-membered or 6-membered N-heterocyclic ring which is aliphatic or aliphatic interrupted
  • R 1 and R 2 are the same or different C 1 -C 6 alkyl groups, C 3 -C 6 cycloalkyl groups, or C 5 -C 6 heterocycloalkyl groups; or
  • one of R 1 and R 2 , but not both, can be H;
  • R 1 and R 2 taken together with the nitrogen atom can be a 5-membered or 6-membered N-heterocyclic ring which is aliphatic or aliphatic interrupted by a ring oxygen or a second ring nitrogen;
  • M is hydrogen or one equivalent of a pharmaceutically acceptable cation, in which case the rest of the molecule is negatively charged; or
  • R 3 and R 4 are defined in the same manner as R 1 and R 2 .
  • the cation can be an ammonium cation or can be derived from a monovalent or divalent metal such as an alkali metal or an alkaline earth metal, such as Na + , K + , or Zn +2 .
  • the group defined by Formula (D-I) is linked to an ionizable hydrogen atom; typically, the hydrogen atom will dissociate at a pH above about 5.0.
  • dithiocarbamates that can be used are: N-methyl,N-ethyldithiocarbamates, hexamethylenedithiocarbamic acid, sodium di( ⁇ -hydroxyethyl)dithiocarbamate, various dipropyl, dibutyl and diamyl dithiocarbamates, sodium N-methyl,N-cyclobutylmethyl dithiocarbamate, sodium N-allyl-N-cyclopropylmethyldithiocarbamate, cyclohexylamyldithiocarbamates, dibenzyl-dithiocarbamates, sodium dimethylene-dithiocarbamate, various pentamethylene dithiocarbamate salts, sodium pyrrolidine-N-carbodithioate, sodium piperidine-N-carbodithioate, sodium morpholine-N-carbo-dithioate, ⁇ -furfuryl dithiocarbamates and imidazoline dithiocarbamate
  • R 1 of Formula (D-I) is a hydroxy-substituted or, preferably, a (bis to penta) polyhydroxy-substituted lower alkyl group having up to 6 carbon atoms.
  • R 1 can be HO—CH 2 —CHOH—CHOH—CHOH—CH 2 —.
  • R 2 can be H or lower alkyl (unsubstituted or substituted with one or more hydroxyl groups). Steric problems can be minimized when R 2 is H, methyl, or ethyl.
  • a particularly preferred compound of this type is an N-methyl-glucamine dithiocarbamate salt, the most preferred cations of these salts being sodium or potassium.
  • Other preferred dithiocarbamates include the alkali or alkaline earth metal salts wherein the anion is di-n-butyldithiocarbamate, di-n-propyldithiocarbamate, pentamethylenedithiocarbamate, or tetramethylene dithiocarbamate.
  • the agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier can be, but is not limited to, an agent selected from the group consisting of:
  • A is somatostatin, thyrotropin releasing hormone (TRH), vasopressin, alpha interferon, endorphin, muramyl dipeptide or ACTH 4-9 analogue; and
  • B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of Formula (D-III) wherein the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-III(a)):
  • bridge is formed using cysteamine and EDAC as the bridge reagents; or a chimeric peptide of the structure of Formula (D-III) wherein the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-III(b)):
  • the bridge is formed using glutaraldehyde as the bridge reagent
  • the bridge of Subformula (D-III(a)) is formed when cysteamine and EDAC are employed as the bridge reagents.
  • the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-IV(b)):
  • U.S. Pat. No. 6,287,792 to Pardridge et al. discloses methods and compositions for delivery of agents across the blood-brain barrier comprising either avidin or an avidin fusion protein bonded to a biotinylated agent to form an avidin-biotin-agent complex.
  • the avidin fusion protein can include the amino acid sequences of proteins such as insulin or transferrin, an anti-receptor monoclonal antibody, a cationized protein, or a lectin.
  • U.S. Pat. No. 6,372,250 to Pardridge discloses methods and compositions for delivery of agents across the blood-brain barrier employing liposomes.
  • the liposomes are neutral liposomes.
  • the surface of the neutral liposomes is pegylated.
  • the polyethylene glycol strands are conjugated to transportable peptides or other targeting agents.
  • Suitable targeting agents include insulin, transferrin, insulin-like growth factor, or leptin.
  • the surface of the liposome could be conjugated with 2 different transportable peptides, one peptide targeting an endogenous BBB receptor and the other targeting an endogenous BCM (brain cell plasma membrane) peptide.
  • Targeting peptides may be endogenous peptide ligands of the receptors, analogues of the endogenous ligand, or peptidomimetic MAbs that bind the same receptor of the endogenous ligand.
  • Transferrin receptor-specific peptidomimetic monoclonal antibodies can be used as transportable peptides.
  • Monoclonal antibodies to the human insulin receptor can be used as transportable peptides.
  • the conjugation agents which are used to conjugate the blood-barrier targeting agents to the surface of the liposome can be any of the well-known polymeric conjugation agents such as sphingomyelin, polyethylene glycol (PEG) or other organic polymers, with PEG preferred.
  • the liposomes preferably have diameters of less than 200 nanometers. Liposomes having diameters of between 50 and 150 nanometers are preferred. Especially preferred are liposomes or other nanocontainers having external diameters of about 80 nanometers.
  • Suitable types of liposomes are made with neutral phospholipids such as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), diphosphatidyl phosphocholine, distearoylphosphatidylethanolamine (DSPE), or cholesterol.
  • POPC 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine
  • DSPE distearoylphosphatidylethanolamine
  • cholesterol cholesterol
  • the transportable peptide is linked to the liposome as follows: A transportable peptide such as insulin or an HIRMAb is thiolated and conjugated to a maleimide group on the tip of a small fraction of the PEG strands; or, surface carboxyl groups on a transportable peptide such as transferrin or a TfRMAb are conjugated to a hydrazide (Hz) moiety on the tip of the PEG strand with a carboxyl activator group such as N-methyl-N′-3(dimethylaminopropyl)carbodiimide hydrochloride (EDAC); a transportable peptide is thiolated and conjugated via a disulfide linker to the liposome that has been reacted with N-succinimidyl 3-(2-pyridylthio)propionate (SPDP); or a transportable peptide is conjugated to the surface of the liposome with avidin-biotin technology, e.g., the
  • U.S. Pat. No. 8,124,095 to Pardridge et al. discloses monoclonal antibodies that are capable of binding to an endogenous blood-brain barrier receptor-mediated transport system and are thus capable of serving as a vector for transport of a therapeutic agent across the BBB.
  • the monoclonal antibody can be, for example, an antibody specifically binding the human insulin receptor on the human BBB.
  • a fusion protein for delivery of a wide variety of agents to a cell via antibody-receptor-mediated endocytosis comprises a first segment and a second segment: the first segment comprising a variable region of an antibody that recognizes an antigen on the surface of a cell that after binding to the variable region of the antibody undergoes antibody-receptor-mediated endocytosis, and, optionally, further comprises at least one domain of a constant region of an antibody; and the second segment comprising a protein domain selected from the group consisting of avidin, an avidin mutein, a chemically modified avidin derivative, streptavidin, a streptavidin mutein, and a chemically modified streptavidin derivative.
  • the antigen is a protein.
  • the protein antigen on the surface of the cell is a receptor such as a transferrin receptor- or an insulin receptor.
  • the invention also includes an antibody construct incorporating the fusion protein that is either a heavy chain or a light chain together with a complementary light chain or heavy chain to form an intact antibody molecule.
  • the therapeutic agent can be a non-protein molecule and can be linked covalently to biotin.
  • the agent that suppresses the growth of cancer stem cells can be, but is not limited to: (1) naphthoquinones; (2) VEGF-DLL4 bispecific antibodies; (3) farnesyl transferase inhibitors; (4) gamma-secretase inhibitors; (5) anti-TIM3 antibodies; (6) tankyrase inhibitors; (7) Wnt pathway inhibitors other than tankyrase inhibitors; (8) camptothecin-binding moiety conjugates; (9) Notch1 binding agents, including antibodies; (10) oxabicycloheptanes and oxabicycloheptenes; (11) inhibitors of the mitochondrial electron transport chains or the mitochondrial tricarboxylic acid cycle; (12) Axl inhibitors; (1
  • Cancer stem cells were first identified in acute myeloid leukemia but since have been identified in many other types of malignancies. Cancer stem cells possess many of the characteristics associated with normal stem cells, in particular the ability to give rise to all cell types found in a particular cancer sample, as well as possibly other cell types. Cancer stem cells are therefore tumorigenic, and may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Cancer stem cells can also undergo clonal evolution through the occurrence of mutations that confer more aggressive properties and their selection.
  • Cancer stem cells are described in G. H. Heppner et al., “Tumor Heterogeneity: Biological Implications and Therapeutic Consequences,” Cancer Metastasis Rev. 2:5-23 (1983); T. Reya et al., “Stem Cells, Cancer, and Cancer Stem Cells,” Nature 414:105-111 (2001); P. B. Gupta et al., “Cancer Stem Cells: Mirage or Reality,” Nature Med. 15:1010-1012 (2009); S. K. Singh et al., “Identification of a Cancer Stem Cell in Human Brain Tumors,” Cancer Res. 63:5821-5828 (2003); M.
  • U.S. Pat. No. 8,871,802 to Jiang et al. discloses naphthoquinones for suppression of cancer stem cell proliferation, including, but not limited to: 2-sulfinyl substituted naphtho[2,3-b]furan-4,9-diones; 2-sulfonyl substituted naphtho[2,3-b]furan-4,9-diones; 2-(1-hydroxy-2-nitroethenyl) substituted naphtho[2,3-b]furan-4,9-diones; 2-(1-hydroxy-2-methylsulfinylethenyl) substituted naphtho[2,3-b]furan-4,9-diones; 2-(1-hydroxy-2-methylsulfonylethenyl) substituted naphtho[2,3-b]furan-4,9-diones; 2-(1-methyl-2-methylsulfinylethenyl) substituted naphtho[2,3-b]fur
  • U.S. Pat. No. 8,853,274 to Wang discloses the use of farnesyl transferase inhibitors and gamma-secretase inhibitors to suppress cancer stem cell proliferation.
  • the use of gamma-secretase inhibitors to suppress cancer stem cell proliferation is also disclosed in United States Patent Application Publication No. 2014/0227173 by Eberhart et al., incorporated herein by this reference.
  • the gamma-secretase inhibitors include compounds of Formula (IV)
  • R 1 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, or (C 1 -C 4 )alkoxy;
  • R 2 is a moiety of Subformula (IV(a))
  • E is CH 2 or NH
  • D is (CH 2 ) m , O(CH 2 ) m , HN(CH 2 ) m , or CH ⁇ CH, wherein m is 0, 1, or 2
  • a and Q are independently N, NCH 3 , or C
  • M is C or C ⁇ O
  • n is 1 or 2
  • Z 1 and Z 2 are independently hydrogen, halogen, halo(C 1 -C 4 )alkyl or phenyl; or Z 1 and Z 2 , when attached to carbon atoms, form a 6-membered aryl ring with the carbon atoms to which they are attached
  • Z 3 is hydrogen, halogen, halo(C 1 -C 4 )alkyl or phenyl.
  • U.S. Pat. No. 8,841,418 to Karsunky et al. discloses the use of anti-TIM3 antibodies to suppress CSC proliferation.
  • the use of anti-TIM3 antibodies is also disclosed in U.S. Pat. No. 8,647,623 to Takayanagi et al., incorporated herein by this reference.
  • U.S. Pat. No. 8,841,299 to Hermann et al. discloses tankyrase inhibitors useful for modulation of the Wnt pathway, including substituted pyrrolo[1,2-a]pyrazines such as, but not limited to, 6-bromo-3-(4-methoxy-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one, 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile, N-hydroxy-1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine, 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-c-arboxamidine, 6-(4,5-d
  • tankyrase inhibitors such as, but not limited to, 7-methyl-2-(4-pyridin-4-yl-piperazin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one, 4-[4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-piperazin-1-yl]-benzoic acid ethyl ester, 2-[4-(4-chloro-phenyl)-piperazin-1-yl]-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one, 7-methyl-2-(4-pyridin-2-yl-piperazin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one, 7-methyl-2-(4-pyridin-2-yl-piperazin-1-yl)-3,7-
  • X is selected from the group consisting of NH, O, S and CH 2
  • the R 1 and/or the R 2 group are independently selected from the group consisting of hydrogen, halo, hydroxy, mercapto, cyano, formyl, alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl.
  • hetero refers to groups that contain one or more heteroatoms selected from the group consisting of O, S, N and combinations thereof.
  • Still other tankyrase inhibitors are disclosed in United States Patent Application Publication No. 2014/0121231 by Bolin et al., incorporated herein by this reference, including pyranopyridone inhibitors of Formula (VIII)
  • X is independently in each occurrence N or CH;
  • Y is S, O, CH or NCH 3 ;
  • R 1 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C(CH 3 ) 2 OH, CN, NO 2 , CO 2 CH 3 , CONH 2 , NH 2 , or halogen; and
  • R 2 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, C 5 -C 12 spiroalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 alkoxy-C 1 -C 6 alkyl, oxetanyl, tetrahydrofuranyl, pyranyl, or SO 2 R 3 wherein R 3 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, oxetanyl, tetrahydrofuranyl, or pyranyl.
  • camptothecin-binding moiety conjugates that can target cancer stem cell antigens such as CD133 or CD44; the conjugates can include a monoclonal antibody as targeting moiety.
  • U.S. Pat. No. 8,834,875 to Van Der Horst discloses Notch1 binding agents, specifically antibodies that specifically bind to a non-ligand binding membrane proximal region of the extracellular domain of human Notch1.
  • Other anti-Notch1 antibodies that can be used for suppression of proliferation of cancer stem cells are disclosed in U.S. Pat. No. 8,784,811 to Lewicki et al., U.S. Pat. No. 8,460,661 to Gurney et al., U.S. Pat. No. 8,435,513 to Gurney et al., and U.S. Pat. No. 8,226,943 to Gurney et al., U.S. Pat. No. 8,088,617 to Gurney et al., U.S. Pat. No. 7,919,092 to Lewicki, all of which are incorporated herein by this reference.
  • U.S. Pat. No. 8,815,844 to Clement et al. discloses inhibitors of the mitochondrial electron transport chains or the mitochondrial tricarboxylic acid cycle for suppression of cancer stem cell proliferation; the inhibitors include rotenone, myxothiazole, stigmatellin, and piericidin.
  • Inhibitors of the receptor protein tyrosine kinase Axl are usable for suppression of cancer stem cell proliferation.
  • Inhibitors of Axl are disclosed in U.S. Pat. No. 8,839,364 to Singh et al., including polycyclic aryl and polycyclic heteroaryl substituted triazoles; U.S. Pat. No.
  • U.S. Pat. No. 8,809,299 by Bhatia et al. discloses a method of suppression of proliferation of cancer stem cells comprising administration of a dopamine receptor antagonist such as thioridazine and a chemotherapeutic agent, such as a DNA synthesis inhibitor such as cytarabine, or a microtubule inhibitor such as paclitaxel or docetaxel.
  • a dopamine receptor antagonist such as thioridazine
  • a chemotherapeutic agent such as a DNA synthesis inhibitor such as cytarabine
  • a microtubule inhibitor such as paclitaxel or docetaxel.
  • Inhibitors or modulators of the Hedgehog pathway are also useful for suppression of proliferation of cancer stem cells.
  • Such inhibitors or modulators are disclosed in U.S. Pat. No. 8,785,635 to Austad et al., including cyclopamine analogs; U.S. Pat. No. 8,669,243 to Dahmane et al., including steroid-derived cyclopamine analogs; U.S. Pat. No. 8,575,141 to Dahmane et al., including steroid-derived cyclopamine analogs; U.S. Pat. No. 8,431,566 to Castro et al., including cyclopamine lactam analogs; U.S. Pat. No.
  • Hedgehog pathway inhibitors are also disclosed in U.S. Pat. No. 8,507,471 to Dierks et al., incorporated herein by this reference, including biphenylcarboxamide derivatives such as N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide.
  • the transmembrane protein Smoothened (Smo) acts as a positive regulator of Hedgehog signaling, and thus inhibitors of Smo also act to inhibit signaling by the Hedgehog pathway.
  • Inhibitors of Smo are disclosed in U.S. Pat. No.
  • pyridazinyl derivatives such as 2-[(R)-4-(4,5-dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol; 2-[(R)-4-(6-(hydroxyl-phenyl-methyl)-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-yl]-propan-2-ol; 2-[(R)-4-(4,5-dimethyl-6-pyridin-4-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol; 2-[(R)-4-(4,5-dimethyl-6
  • Antibodies that bind GRP94 can also be used to suppress cancer stem cell proliferation. Such antibodies are disclosed in U.S. Pat. No. 8,771,687 to Ferrone et al., incorporated herein by this reference, and can be used together with a BRAF inhibitor such as vemurafenib or PLX4720 (N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide).
  • a BRAF inhibitor such as vemurafenib or PLX4720 (N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide).
  • Frizzled receptor polypeptides can also be used to suppress cancer stem cell proliferation.
  • Such Frizzled receptor polypeptides can comprise a soluble receptor that comprises a Fri domain of a FZD receptor that binds a ligand of a human FZD receptor and is capable of inhibiting tumor growth, and are disclosed in U.S. Pat. No. 8,765,913 to Gurney et al., incorporated herein by this reference.
  • anti-frizzled receptor antibodies can be used to suppress cancer stem cell proliferation, and are disclosed in U.S. Pat. No. 8,507,442 to Gurney et al., incorporated herein by this reference.
  • anti-prominin-1 antibody having ADCC activity or CDC activity to suppress cancer stem cell proliferation is disclosed in U.S. Pat. No. 8,722,858 to Yoshida, incorporated herein by this reference.
  • antibodies specifically binding N-cadherin to suppress cancer stem cell proliferation is disclosed in U.S. Pat. No. 8,703,920 to Reiter et al., incorporated herein by this reference.
  • the antibodies can be fully human antibodies.
  • DR5 agonists to suppress cancer stem cell proliferation is disclosed in U.S. Pat. No. 8,703,712 to Buchsbaum et al., incorporated herein by this reference.
  • the DR5 agonist can be a DR5 antibody.
  • anti-DLL4 antibodies or binding fragments thereof to suppress cancer stem cell proliferation is disclosed in U.S. Pat. No. 8,685,401 to Harris et al., incorporated herein by this reference.
  • the antibodies or binding fragments can be used together with radiation.
  • DLL4 is a Notch ligand.
  • anti-DLL4 antibodies is also disclosed in U.S. Pat. No. 8,663,636 to Foltz et al., incorporated herein by this reference; the antibodies include fully human antibodies.
  • anti-DLL4 antibodies is also disclosed in U.S. Pat. No. 8,192,738 to Bedian et al., incorporated herein by this reference; the antibodies can include fully human antibodies.
  • GPR49 is a member of the LGR family and is a hormone receptor.
  • Anti-GPR49 antibodies are also disclosed in United States Patent Application Publication No. 2014/0302054 by Reyes et al. and in United States Patent Application Publication No. 2014/0256041 by Reyes et al., both incorporated herein by this reference. These antibodies can be monoclonal, humanized, or fully human antibodies.
  • DDR1 binding agents including antibodies, that can be used to suppress cancer stem cell proliferation.
  • the antibodies bind to an extracellular domain of DDR1 and modulate DDR1 activity.
  • R 1 to R 9 are the same or different, H, D, OH, halogen, nitro, CN, nitrileamido, amidosulfide, amino, aldehyde, substituted ketone, —COOH, ester, trifluoromethyl, amide, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, arylsulfonyl, arylalkylenesulfonyl, alkoxy, alkylalkoxy, haloalkyl, alkylhaloalkyl, haloaryl, aryloxy, amino, monoalkylamino, dialkylamino, alkylamido, arylamino, arylamido, alkylthio, arylthio, heterocycloalkyl, alkylheterocycl
  • U.S. Pat. No. 8,591,892 to Alinari et al. discloses methods for suppression of proliferation of cancer stem cells by administration of fingolimod and anti-CD74 antibodies or fragments thereof.
  • the use of anti-CD74 antibodies to suppress cancer stem cell proliferation is also disclosed in U.S. Pat. No. 8,367,037 to Byrd et al. and in U.S. Pat. No. 8,119,101 to Byrd et al., both incorporated herein by this reference.
  • M is O or S
  • R 1 is selected from H, F, Cl, Br, I, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfonic acid, sulfonic ester, sulfonamide, N-
  • R 2 is selected from the group consisting of Subformulas (X(a)) and (X(b))
  • n 1;
  • R b is hydrogen or independently at each instance any group selected from F, Cl, Br, I, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sul
  • R 3 is selected from H, F, Cl, Br, I, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfonic acid, sulfonic este
  • R 4 is selected from the group consisting of from H, F, Cl, Br, I, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid,
  • Cyc is selected from the group consisting of aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, and substituted carbocycle.
  • U.S. Pat. No. 8,530,429 to Robbins et al. discloses a method for suppression of cancer stem cell proliferation, particularly for glioblastoma multiforme, comprising administration of peptides that bind to cancer stem cells.
  • the peptides are between 12 and 20 amino acids, and are conjugated to an anti-tumor agent.
  • the peptides can be comprised of L-amino acids, D-amino acids, a mixture of L- and D-amino acids, or a retro-inverso peptide formed of D-amino acids arranged in reverse order.
  • U.S. Pat. No. 8,470,307 to Frankel discloses the use of a diphtheria toxin-interleukin 3 conjugate to suppress cancer stem cell proliferation.
  • the conjugate is a fusion protein comprising amino acids 1-388 of diphtheria toxin fused via a peptide linker to full-length, human interleukin-3.
  • HDAC histone deacetylase
  • n 1-10;
  • X is C—R 11 or N, wherein R 11 is H, OH, SH, F, Cl, SO 2 R 7 , NO 2 , trifluoromethyl, methoxy, or CO—R 7 , wherein R 7 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • R 2 is H or NR 3 R 4 , wherein R 3 and R 4 are each independently H or C 2 -C 6 alkyl;
  • R 5 is SH
  • R 6 , R 12 , R 13 , and R 14 are each independently H, OH, SH, F, Cl, SO 2 R 15 , NO 2 , trifluoromethyl, methoxy, or CO—R 15 , wherein R 15 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound of Formula (XI).
  • U.S. Pat. No. 8,435,972 to Stein et al. discloses the use of progesterone and analogs and derivatives thereof to suppress cancer stem cell proliferation, including pregnenolone, dehydroepiandrosterone, allopregnanolone tetrahydrodeoxycorticosterone, alphaxolone, alphadolone, hydroxydione, minaxolone, ganaxolone, and 3 ⁇ -hydroxy-5 ⁇ -pregnane-20-one, and their sulfates.
  • U.S. Pat. No. 8,404,239 to Siebel et al. discloses antibodies that bind the negative regulatory region (NRR) of Notch2.
  • the antibodies can be monoclonal antibodies.
  • the antibodies can be used to suppress cancer stem cell proliferation.
  • Antibodies that bind other regions of Notch2, such as a non-ligand binding region are disclosed in U.S. Pat. No. 8,206,713 to Lewicki et al., incorporated herein by this reference, and can be used to suppress cancer stem cell proliferation.
  • the antibodies can be monoclonal antibodies, chimeric antibodies, humanized antibodies, or human antibodies. Still other antibodies that bind Notch2 are disclosed in United States Patent Application Publication No. 2014/0314782 by Christian et al., incorporated herein by this reference, and can be used to suppress cancer stem cell proliferation.
  • HGFIN protein receptor
  • inhibitors of HGFIN can be used to suppress cancer stem cell proliferation and can also be used to reverse carboplatin resistance.
  • U.S. Pat. No. 8,299,106 to Li et al. discloses thiazole-substituted indolin-2-ones that are inhibitors of CSCPK and related kinases, and that can be used to suppress cancer stem cell proliferation. Additional inhibitors of CSCPK and related kinases are disclosed in United States Patent Application Publication No. 2014/0275033 by Li et al., incorporated herein by this reference.
  • HnRNPG Heterogeneous Ribonucleoprotein G
  • U.S. Pat. No. 8,163,279 to Bergstein discloses antibodies binding to the ILR3 ⁇ subunit that can be used to suppress cancer stem cell proliferation.
  • the antibodies can be conjugated to a cytotoxic agent.
  • U.S. Pat. No. 8,058,243 to Tyers et al. discloses the use of a compound selected from the group consisting of ( ⁇ )butaclamol, R( ⁇ ) propylnorapomorphine, apomorphine, cis-(Z) flupenthixol, hexahydro-sila-difenidol, ifenprodil tartrate, carbetapentane citrate, fenretinide, WHI-P131, SB 202190, p-aminophenethyl-m-trifluoromethylphenyl piperazine (PAPP), and dihydrocapsaicin to suppress cancer stem cell proliferation.
  • a particularly preferred compound is ifenprodil tartrate.
  • U.S. Pat. No. 7,790,407 to Ma discloses antibodies specific for SALL4, including isoforms SALL4A, SALL4B, and SALL4C.
  • SALL4 is a zinc finger transcription factor.
  • the antibodies can be used to suppress cancer stem cell proliferation.
  • U.S. Pat. No. 7,754,206 to Clarke et al. discloses antibodies specifically binding Notch4 that modulate the activity of a Notch4 ligand, such as Delta 1, Delta 2, Delta-like ligand 4 (D114), Jagged 1 or Jagged 2.
  • the antibodies can be used to suppress cancer stem cell proliferation.
  • United States Patent Application Publication No. 2014/0314836 by Doxsey et al. discloses a method of suppressing cancer stem cell proliferation by inducing degradation of a midbody derivative in cells by increasing the amount of Neighbor of BRCA1 (NBR1) in the cell or potentiating binding between NBR1 and Centrosomal Protein of 55 kDa (Cep55) in the cell. This can be done by employing a bispecific antibody that binds to both NBR1 and Cep55.
  • NBR1 Neighbor of BRCA1
  • Cep55 Centrosomal Protein of 55 kDa
  • United States Patent Application Publication No. 2014/0309184 by Rocconi et al. discloses a method for suppressing cancer stem cell proliferation by administration of a Smo inhibitor, such as N-[2-methyl-5-[(methylamino)methyl]phenyl]-4-[(4-phenyl-2-quinazolinyl)amino]-benzamide (BMS-833923), and a chemotherapeutic agent such as a platinum-based therapeutic agent.
  • a Smo inhibitor such as N-[2-methyl-5-[(methylamino)methyl]phenyl]-4-[(4-phenyl-2-quinazolinyl)amino]-benzamide (BMS-833923)
  • a chemotherapeutic agent such as a platinum-based therapeutic agent.
  • X 1 is N or CH
  • A is selected from the group consisting of a valence bond, (C 1 -C 20 ) hydrocarbyl, (C 1 -C 20 ) oxaalkyl, and (C 1 -C 20 ) azaalkyl;
  • R 1 is selected from the group consisting of hydrogen, —C( ⁇ NH)NH 2 , —C( ⁇ NH)NH(C 1 -C 10 )hydrocarbyl, fluoro(C 1 -C 6 )hydrocarbyl, and —CH(NH 2 )COOH, with the provisos that: (a) when A is a valence bond, R 1 cannot be H; and (b) when QR 3 is OH, R 1 cannot be fluoro(C 1 -C 6 )hydrocarbyl;
  • R 2 is selected from the group consisting of hydrogen, —C( ⁇ NH)NH 2 , —C( ⁇ NH)NH(C 1 -C 10 )hydrocarbyl, fluoro(C 1 -C 6 )hydrocarbyl, and —CH(NH 2 )COOH;
  • R 3 is selected from the group consisting of hydrogen and (C 1 -C 20 ) hydrocarbyl
  • n 1 or 2.
  • United States Patent Application Publication No. 2014/0302034 by Bankovich et al. discloses antibodies that specifically bind to EFNA1; the antibodies can include multispecific antibodies and can be humanized. The antibodies can be used to suppress proliferation of cancer stem cells.
  • United States Patent Application Publication No. 2014/0294994 by Huang discloses antipsychotic phenothiazine derivatives for suppression of cancer stem cell proliferation.
  • the derivatives can be, but are not limited to, trifluoperazine, chlorpromazine, thioridazine, perphenazine, triflupromazine, or promazine.
  • the derivatives can be used with another antineoplastic agent such as gefitinib or cisplatin.
  • HDAC6 inhibitors include tubacin, tubastatin A, and cyclic tetrapeptide hydroxamic acids.
  • Suitable AKT inhibitors include BEZ-235, PI-103, API-2, LY294002, Wortmannin, AKT VIII, BKM120, BGT226, Everolimus, Choline kinase inhibitors, bcl-2 inhibitors, Hsp-90 inhibitors, multi-kinase inhibitors, mTOR kinase inhibitors, proteasome inhibitors, and TORC1/TORC2 inhibitors.
  • United States Patent Application Publication No. 2014/0286961 by Bergstein discloses a method of suppressing proliferation of cancer stem cells employing administration of a ligand that binds to a cancer-stem-line-specific cell surface antigen stem cell marker, wherein the antigen is selected from the group consisting of CD34, Scl/Tal-1, Flk-1/KDR, Tie-1, Tie-2, c-Kit, AC133, PU.1, ikaros, beta-1 alpha (2,3,5) integrin, cytokeratin 19, basonuclin, skin 1a-i/Epoc-1/Oct11, cytokeratin 14, LEF-1, SP-1, SP-2, EGF-R, MUC-1, c-Kit, SCF, Ag/s270.38, 374.3, 18.11, AFP, IGF-2, TGF-alpha/beta, GGT, Isl-1, FA-1, TRA-1-60, SSEA (1,3,4), BCL-2,
  • binding agents including antibodies, that bind human MET.
  • the antibodies can be bispecific, with a second binding site binding one or more components of the Wnt pathway; the second binding site can be a soluble human frizzled 8 (FZD8) FZD8 receptor.
  • the binding agents can be used for suppression of proliferation of cancer stem cells.
  • PDGFR- ⁇ inhibitor to suppress proliferation of cancer stem cells.
  • the PDGFR- ⁇ inhibitor can be sunitinib, axitinib, BIBF1120, MK-2461, dovitinib, pazopanib, telatinib, CP 673451, or TSU-68.
  • United States Patent Application Publication No. 2014/0220159 by Arora et al. discloses hydrogen-bond surrogate peptides and peptidomimetics that reactivate p53 and that can be used for suppressing proliferation of cancer stem cells.
  • United States Patent Application Publication No. 2014/0205655 by Arora et al. similarly discloses oligooxopiperazines for reactivating p53, such as oligooxopiperazines that substantially mimic helix ⁇ B of the C-terminal transactivation domain of Hypoxia-Inducible Factor 1 ⁇ and that can be used for suppressing proliferation of cancer stem cells.
  • United States Patent Application Publication No. 2014/0193358 by Merchant discloses a method for targeting cancer stem cells comprising administering to the subject a targeted cargo protein, wherein the targeted cargo protein comprises: (a) one or more cargo moieties; and (b) one or more targeting moieties that bind to a target displayed by a cancer stem cell, wherein the targeting moiety is derived from a natural ligand to the target.
  • the cargo moiety can comprise a toxin
  • the targeting moiety can comprise a pro-apoptosis member of the BCL-2 family selected from BAX, BAD, BAT, BAK, BIK, BOK, BID BIM, BMF and BOK.
  • the biguanide derivatives include N 1 -piperidine-N 5 -(3-bromo)phenyl biguanide; N 1 -piperidine-N 5 -phenyl biguanide; N 1 -piperidine-N 5 -(3-methyl)phenyl biguanide; N 1 -piperidine-N 5 -(3-ethyl)phenyl biguanide; N 1 -piperidine-N 5 -(3-hydroxy)phenyl biguanide; N 1 -piperidine-N 5 -(3-hydroxymethyl)phenyl biguanide; N 1 -piperidine-N 5 -(3-methoxy)phenyl biguanide; N 1 -piperidine-N 5 -(4-fluoro)phenyl biguanide; N 1 -piperidine-N 5 -(2-fluoro)phenyl biguanide; N 1 -piperidine-N 5 -(3-
  • (1) is a single or double bond
  • R is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 7 , CH 2 R 7 , CH 2 C(O)R 7 , or CH 2 C(O)NHR 7 ;
  • R 1 is H, OR 8 , or OCH 2 COOR 8 ;
  • R 2 is H, OR 8 , or OCH 2 COOR 8 ;
  • R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OCH 2 COOR 8 , or OS(O) 2 R 7 NHC(O)R 8 ; or R 2 and R 3 can combine to form —OCH 2 O—;
  • R 4 is H or halogen
  • R 5 is H or OR 8 , or R 4 and R 5 can combine to form a 6-membered aryl ring;
  • R 6 is optional, and, if present, is COOR 8 ;
  • R 7 is a monocyclic or polycyclic aryl, or a monocyclic or polycyclic heterocyclyl or heteroaryl containing 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 7 being optionally substituted from 1-3 times with substituents selected from the group consisting of halogen, COOR 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • X is S, O, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • Y is S or C.
  • A is O or C
  • L 1 is independently selected from the group consisting of: (a) absent; (b) —C(S)NH—, and (c) a moiety of Subformula (XV(a))
  • L 2 is NH or O
  • L 3 is absent or —CH 2 —
  • L 4 is absent or —R 24 ⁇ N—N ⁇ CH—;
  • L 5 is absent or —C(O)—
  • R 10 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R 11 is H, halogen, NO 2 , OCH 2 COOR 23 , OC(O)R 23 , or OR 23 ;
  • R 12 is H or OR 23 ;
  • R 13 is H
  • R 14 is H, OR 23 , C(O)NH 2 , or COOR 23 ;
  • R 15 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or COOR 23 ;
  • R 16 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —CH ⁇ R 24 , or COOR 23 ;
  • R 17 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or COOR 23 ;
  • R 18 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 23 , or COOR 23 ;
  • R 20 is —NH—, —NH—N—CH—, or NH 2 ;
  • R 21 is —(CH2) n —, where n is 0 to 6;
  • R 22 is —CH— or —CHR 24 ;
  • R 23 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R 24 is a monocyclic or polycyclic aryl, or a monocyclic or polycyclic heterocyclyl or heteroaryl containing 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 24 being optionally substituted from 1-3 times with substituents selected from the group consisting of OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, ⁇ O, ⁇ NH, NH 2 , halogen, and COOR 23 .
  • United States Patent Application Publication No. 2014/0094466 by Haga et al. discloses inhibitors of Slingshot-2 that can be used to suppress proliferation of cancer stem cells.
  • the inhibitors include 3-[(4,5-dimethoxy-3-oxo-1H-isobenzofuran-1-yl)amino]-4-methylbenzoic acid; 2-ethoxy-5-(4-phenylpiperidine-1-sulfonyl)benzoic acid; and 3-[bis(2-methoxyethyl)sulfamoyl]benzoic acid.
  • each B is independently hydrogen or a moiety of Subformula (XVI(a))
  • At least one B is hydrogen and not more than one B is hydrogen; D is selected from —NH, —N-lower alkyl, or O; and n is 0-2.
  • CCR5 antagonists that can be used for suppressing proliferation of cancer stem cells.
  • the CCR5 antagonists include 4,4-difluoro-N-[(1S)-3-[(1R,5S)-3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide; (4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone; 4,4-difluoro-N-[(1 S)-3-[(1R,5
  • United States Patent Application Publication No. 2013/0295118 by Jiang et al. discloses antibodies that specifically bind the extracellular domain of human C-type lectin-like molecule (CLL-1).
  • the antibodies can be used for suppression of cancer stem cell proliferation.
  • the antibodies can be humanized and can be conjugated to a therapeutic compound.
  • United States Patent Application Publication No. 2013/0287688 by Jain et al. discloses the use of anti-hypertension compounds for suppression of cancer stem cell proliferation.
  • the anti-hypertension compounds include losartan, candesartan, eprosartan mesylate, EXP 3174, irbesartan, L158,809, olmesartan, saralasin, telmisartin, valsartan, aliskiren, remikiren, enalkiren, SPP635, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, ABT-510, CVX-045, LSKL, DN-9693, and FG-3019.
  • anti-hypertension compounds include an angiotensin II receptor blocker, an antagonist of renin angiotensin aldosterone system, an angiotensin converting enzyme (ACE) inhibitor, a thrombospondin 1 (TSP-1) inhibitor, a transforming growth factor 31 inhibitor, a stromal cell-derived growth factor 1 ⁇ inhibitor, or a connective tissue growth factor (CTGF) inhibitor.
  • angiotensin II receptor blocker an antagonist of renin angiotensin aldosterone system
  • ACE angiotensin converting enzyme
  • TSP-1 thrombospondin 1
  • transforming growth factor 31 inhibitor transforming growth factor 31 inhibitor
  • stromal cell-derived growth factor 1 ⁇ inhibitor a stromal cell-derived growth factor 1 ⁇ inhibitor
  • CTGF connective tissue growth factor
  • anthraquinone radiosensitizer agents that can be used together with ionizing radiation to suppress cancer stem cell proliferation.
  • the anthraquinone radiosensitizer agents include hexamethyl hypericin, hypericin tetrasulfonic acid, and tetrabromohypericin.
  • the derivatives include 4-amino-6-bromo-1-((2S,3R,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidinone-5-carboxamide; ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidinone-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl isobutylate; ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidinone-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl pivalate; (2S,3R,4S,5S)-2
  • CDK8 antagonists that can be used to suppress cancer stem cell proliferation.
  • the CDK8 antagonists include flavopiridol, ABT-869, AST-487, BMS-387032/SNS032, BIRB-796, sorafenib, staurosporine, cortistatin, cortistatin A, and a steroidal alkaloid or derivative thereof.
  • United States Patent Application Publication No. 2013/0210024 by Yu et al. discloses a method of cancer treatment, including suppression of proliferation of cancer stem cells, by activating FBOX32 expression through the inhibition of the histone methyltransferase EZH2.
  • the EZH2 inhibitor can be isoliquiritigenin or 3-Deazaneplanocin A.
  • the sulfonamides include 4- ⁇ [(benzylamino)carbonyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(benzhydrylamino) carbonyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(4′-fluorophenyl)carbamoyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(4′-bromophenyl)carbamoyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(2′-methoxyphenyl)carbamoyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(2′-isopropylphenyl)carbamoyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(4′-isopropylphenyl)carbamoyl]amino ⁇ benzenesulfonamide; 4- ⁇ [(4′-isopropylphenyl)
  • Inhibitors of mTOR are well known in the art, and include, but are not limited to: sirolimus: temsirolimus, everolimus; rapamune; ridaforolimus; AP23573 (deforolimus); CCI-779 (rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid); AZD8055 ((5-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methanol); PKI-587 (1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)
  • United States Patent Application Publication No. 2013/0095104 by Cummings et al. discloses antibodies, including monoclonal antibodies or antigen-binding fragments thereof, specifically binding to FZD10.
  • the antibodies can be conjugated to an antineoplastic agent.
  • United States Patent Application Publication No. 2014/0322128 by Maltese et al. discloses compounds useful for suppression of cancer stem cell proliferation by induction of methuosis.
  • the compounds include trans-3-(2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one; trans-3-(1H-indol-3-yl)-1-phenyl-2-propen-1-one; trans-3-(1H-indol-3-yl)-1-(2-pyridinyl)-2-propen-1-one; trans-3-(1H-indol-3-yl)-1-(3-pyridinyl)-2-propen-1-one; trans-3-(1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one; trans-3-(5-methoxy-1H-indol-3-yl)-1-(4-pyri
  • compositions to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy employing a substituted hexitol derivative for the treatment of NSCLC or GBM comprising an alternative selected from the group consisting of:
  • a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage form wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage form possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC or GBM as compared with an unmodified substituted hexitol derivative;
  • a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage kit and packaging wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage kit and packaging possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC or GBM as compared with an unmodified substituted hexitol derivative;
  • a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is subjected to a bulk drug product improvement wherein substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative subjected to the bulk drug product improvement possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC or GBM as compared with an unmodified substituted hexitol derivative.
  • the unmodified substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the unmodified substituted hexitol derivative is dianhydrogalactitol.
  • composition comprises a drug combination comprising:
  • an additional therapeutic agent selected from the group consisting of:
  • composition comprises:
  • a therapeutic agent subject to chemosensitization selected from the group consisting of:
  • composition comprises:
  • a therapeutic agent subject to chemopotentiation selected from the group consisting of:
  • the substituted hexitol derivative is subjected to a bulk drug product improvement, wherein the bulk drug product improvement is selected from the group consisting of:
  • composition comprises a substituted hexitol derivative and a diluent, wherein the diluent is selected from the group consisting of:
  • composition comprises a substituted hexitol derivative and a solvent system, wherein the solvent system is selected from the group consisting of:
  • composition comprises a substituted hexitol derivative and an excipient, wherein the excipient is selected from the group consisting of:
  • substituted hexitol derivative is incorporated into a dosage form selected from the group consisting of:
  • the substituted hexitol derivative is incorporated into a dosage kit and packaging selected from the group consisting of amber vials to protect from light and stoppers with specialized coatings to improve shelf-life stability.
  • the dosage kit and packaging can be labeled to indicate details of use and may contain one or more than one therapeutically active agent; if more than one therapeutic agent is included, the two or more therapeutic agents can be combined or separately packaged.
  • composition comprises a substituted hexitol derivative and a drug delivery system selected from the group consisting of:
  • the substituted hexitol derivative is present in the composition in a drug conjugate form selected from the group consisting of:
  • the therapeutic agent is a modified substituted hexitol derivative and the modification is selected from the group consisting of:
  • the substituted hexitol derivative is in the form of a prodrug system, wherein the prodrug system is selected from the group consisting of:
  • the composition comprises a substituted hexitol derivative and at least one additional therapeutic agent to form a multiple drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of:
  • the composition comprises a substituted hexitol derivative and an agent to counteract myelosuppression as described above.
  • the agent to counteract myelosuppression is a dithiocarbamate.
  • the composition comprises a substituted hexitol derivative and an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier as described above.
  • the agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier is an agent selected from the group consisting of:
  • A is somatostatin, thyrotropin releasing hormone (TRH), vasopressin, alpha interferon, endorphin, muramyl dipeptide or ACTH 4-9 analogue; and
  • B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of Formula (D-III) wherein the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-III(a)):
  • bridge is formed using cysteamine and EDAC as the bridge reagents; or a chimeric peptide of the structure of Formula (D-III) wherein the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-III(b)):
  • the bridge is formed using glutaraldehyde as the bridge reagent
  • the composition comprises a substituted hexitol derivative and an agent that suppresses proliferation of cancer stem cells, wherein the agent that suppresses proliferation of cancer stem cells is selected from the group consisting of: (1) naphthoquinones; (2) VEGF-DLL4 bispecific antibodies; (3) farnesyl transferase inhibitors; (4) gamma-secretase inhibitors; (5) anti-TIM3 antibodies; (6) tankyrase inhibitors; (7) Wnt pathway inhibitors other than tankyrase inhibitors; (8) camptothecin-binding moiety conjugates; (9) Notch1 binding agents, including antibodies; (10) oxabicycloheptanes and oxabicycloheptenes; (11) inhibitors of the mitochondrial electron transport chains or the mitochondrial tricarboxylic acid cycle; (12) Axl inhibitors; (13) dopamine receptor antagonists; (14) anti-RSPO1 antibodies; (15) inhibitors or modulators of the Hedgehog pathway; (16) caffeic acid analogs
  • a pharmaceutical composition according to the present invention includes a prodrug
  • prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
  • the pharmacologically active compound in a pharmaceutical composition according to the present invention possesses a sufficiently acidic, a sufficiently basic, or both a sufficiently acidic and a sufficiently basic functional group, these group or groups can accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the pharmacologically active compound with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenz
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as glycine and arginine
  • ammonia such as glycine and arginine
  • primary, secondary, and tertiary amines such as piperidine, morpholine and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • a given pharmacologically active agent such as a substituted hexitol derivative such as dianhydrogalactitol or an analog or derivative of dianhydrogalactitol as described above
  • a pharmaceutical composition according to the present invention will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • such pharmaceutical compositions include a therapeutically effective quantity of the pharmacologically active agent and an inert pharmaceutically acceptable carrier or diluent.
  • compositions are prepared in unit dosage form appropriate for the chosen route of administration, such as oral administration or parenteral administration.
  • a pharmacologically active agent as described above can be administered in conventional dosage form prepared by combining a therapeutically effective amount of such a pharmacologically active agent as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • a variety of pharmaceutical forms can be employed.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup,
  • a pharmaceutically acceptable salt of a pharmacologically active agent as described above is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable cosolvent or combinations of cosolvents.
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
  • a compound of Formula I is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease and/or condition being treated.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • the selected dosage level depends upon a variety of pharmacokinetic factors including the activity of the particular therapeutic agent, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the severity of the condition, other health considerations affecting the subject, and the status of liver and kidney function of the subject.
  • an exemplary daily dose generally employed is from about 0.001 to about 3000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. In some embodiments, the daily dose is from about 1 to 3000 mg/kg of body weight. Other dosages are as described above.
  • Typical daily doses in a patient may be anywhere between about 500 mg to about 3000 mg, given once or twice daily, e.g., 3000 mg can be given twice daily for a total dose of 6000 mg.
  • the dose is between about 1000 to about 3000 mg.
  • the dose is between about 1500 to about 2800 mg.
  • the dose is between about 2000 to about 3000 mg.
  • doses are from about 1 mg/m 2 to about 40 mg/m 2 .
  • doses are from about 5 mg/m 2 to about 25 mg/m 2 . Additional alternatives for dosages are as described above with respect to schedules of administration and dose modification. Dosages can be varied according to the therapeutic response.
  • Plasma concentrations in the subjects may be between about 100 ⁇ M to about 1000 ⁇ M. In some embodiments, the plasma concentration may be between about 200 ⁇ M to about 800 ⁇ M. In other embodiments, the concentration is about 300 ⁇ M to about 600 ⁇ M. In still other embodiments the plasma concentration may be between about 400 to about 800 ⁇ M. In another alternative, the plasma concentration can be between about 0.5 ⁇ M to about 20 ⁇ M, typically 1 ⁇ M to about 10 ⁇ M. Administration of prodrugs is typically dosed at weight levels, which are chemically equivalent to the weight levels of the fully active form.
  • compositions of the invention may be manufactured using techniques generally known for preparing pharmaceutical compositions, e.g., by conventional techniques such as mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.
  • the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, solutions, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • compositions for parenteral administration can include aqueous solutions or suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or modulators which increase the solubility or dispersibility of the composition to allow for the preparation of highly concentrated solutions, or can contain suspending or dispersing agents.
  • compositions for oral use can be obtained by combining the pharmacologically active agent with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating modulators may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • antioxidants such as sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl- ⁇ -naphthylamine, or lecithin
  • chelators such as EDTA can be used.
  • Other ingredients that are conventional in the area of pharmaceutical compositions and formulations, such as lubricants in tablets or pills, coloring agents, or flavoring agents, can be used.
  • conventional pharmaceutical excipients or carriers can be used.
  • the pharmaceutical excipients can include, but are not necessarily limited to, calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Other pharmaceutical excipients are well known in the art.
  • Exemplary pharmaceutically acceptable carriers include, but are not limited to, any and/or all of solvents, including aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and/or antifungal agents, isotonic and/or absorption delaying agents, and/or the like. The use of such media and/or agents for pharmaceutically active substances is well known in the art.
  • compositions should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office of Biologics Standards or by other regulatory organizations regulating drugs.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days; in other alternatives, depending on the therapeutic agent and the formulation employed, release may occur over hours, days, weeks, or months.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid- or gel-phase carriers or excipients.
  • suitable solid- or gel-phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • a pharmaceutical composition can be administered by a variety of methods known in the art.
  • the routes and/or modes of administration vary depending upon the desired results.
  • the pharmacologically active agent may be coated in a material to protect the targeting composition or other therapeutic agent from the action of acids and other compounds that may inactivate the agent.
  • Conventional pharmaceutical practice can be employed to provide suitable formulations or compositions for the administration of such pharmaceutical compositions to subjects. Any appropriate route of administration can be employed, for example, but not limited to, intravenous, parenteral, intraperitoneal, intravenous, transcutaneous, subcutaneous, intramuscular, intraurethral, or oral administration.
  • either systemic or localized delivery of the pharmaceutical composition can be used in the course of treatment.
  • the pharmaceutical composition as described above can be administered together with additional therapeutic agents intended to treat a particular disease or condition, which may be the same disease or condition that the pharmaceutical composition is intended to treat, which may be a related disease or condition, or which even may be an unrelated disease or condition.
  • compositions according to the present invention can be prepared in accordance with methods well known and routinely practiced in the art. See, e.g., Remington: The Science and Practice of Pharmacy , Mack Publishing Co., 20 th ed., 2000; and Sustained and Controlled Release Drug Delivery Systems , J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. Pharmaceutical compositions are preferably manufactured under GMP conditions. Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for molecules of the invention include ethylene-vinyl acetate copolymer particles, osmotic pumps, and implantable infusion systems.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, e.g., polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can be oily solutions for administration or gels.
  • compositions according to the present invention are usually administered to the subjects on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by therapeutic response or other parameters well known in the art. Alternatively, the pharmaceutical composition can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life in the subject of the pharmacologically active agent included in a pharmaceutical composition. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some subjects may continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the subject can be administered a prophylactic regime.
  • treatment can be monitored by observing one or more of the improving symptoms associated with the disease, disorder, or condition being treated, or by observing one or more of the improving clinical parameters associated with the disease, disorder, or condition being treated.
  • the clinical parameters can include, but are not limited to, reduction in tumor burden, reduction in pain, improvement in lung function, improvement in Karnofsky Performance Score, and reduction in occurrence of tumor spread or metastasis.
  • treatment treating, “treating,” or equivalent terminology are not intended to imply a permanent cure for the disease, disorder, or condition being treated.
  • compositions and methods according to the present invention are not limited to treatment of humans, but are applicable to treatment of socially or economically important animals, such as dogs, cats, horses, cows, sheep, goats, pigs, and other animal species of social or economic importance. Unless specifically stated, compositions and methods according to the present invention are not limited to the treatment of humans.
  • the sustained-release or controlled-release formulation can be (1) an oral matrix sustained-release or controlled-release formulation; (2) an oral multilayered sustained-release or controlled-release tablet formulation; (3) an oral multiparticulate sustained-release or controlled-release formulation; (4) an oral osmotic sustained-release or controlled-release formulation; (5) an oral chewable sustained-release or controlled-release formulation; or (6) a dermal sustained-release or controlled-release patch formulation.
  • formulations for controlled release or sustained release comprising a pharmacologically active agent according to the present invention by modifying the formulations described above, such as according to principles disclosed in V. H. K. Li et al, “Influence of Drug Properties and Routes of Drug Administration on the Design of Sustained and Controlled Release Systems” in Controlled Drug Delivery: Fundamentals and Applications (J. R. Robinson & V. H. L. Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 1, pp. 3-94, incorporated herein by this reference.
  • This process of preparation typically takes into account physicochemical properties of the pharmacologically active agent, such as aqueous solubility, partition coefficient, molecular size, stability, and nonspecific binding to proteins and other biological macromolecules.
  • This process of preparation also takes into account biological factors, such as absorption, distribution, metabolism, duration of action, the possible existence of side effects, and margin of safety, for the pharmacologically active agent. Accordingly, one of ordinary skill in the art could modify the formulations into a formulation having the desirable properties described above for a particular application.
  • another aspect of the present invention is a method of treating NSCLC or GBM comprising the step of administering a therapeutically effective quantity of a substituted hexitol derivative such as dianhydrogalactitol to a patient suffering from the malignancy.
  • a substituted hexitol derivative such as dianhydrogalactitol
  • the substituted hexitol derivative can be selected from the group consisting of galactitols, substituted galacitols, dulcitols, and substituted dulcitols.
  • the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol.
  • the substituted hexitol derivative is dianhydrogalactitol.
  • the therapeutically effective quantity of dianhydrogalactitol is from about 1 mg/m 2 to about 40 mg/m 2 .
  • the therapeutically effective quantity of dianhydrogalactitol is from about 5 mg/m 2 to about 25 mg/m 2 .
  • Therapeutically active quantities of substituted hexitol derivatives other than dianhydrogalactitol can be determined by one of ordinary skill in the art by using the molecular weight of the particular substituted hexitol derivative and the activity of the particular substituted hexitol derivative, such as the in vitro activity of the substituted hexitol derivative against a standard cell line. Other suitable dosages are described above with respect to dose modification and schedule of administration and also in the Examples.
  • the substituted hexitol derivative such as dianhydrogalactitol is administered by a route selected from the group consisting of intravenous and oral.
  • the substituted hexitol derivative such as dianhydrogalactitol is administered intravenously.
  • the method can further comprise the step of administering a therapeutically effective dose of ionizing radiation.
  • the method can further comprise the step of administering a therapeutically effective dose of an additional chemotherapeutic agent selected from the group consisting of cisplatin, carboplatin, bevacizumab, paclitaxel, AbraxaneTM (paclitaxel bound to albumin as a delivery vehicle), docetaxel, etoposide, gemcitabine, vinorelbine tartrate, and pemetrexed. Suitable methods for administration of these agents and suitable dosages are well known in the art.
  • the method can also further comprise the step of administering a therapeutically effective quantity of a corticosteroid.
  • the method can also further comprise the step of administering a therapeutically effective quantity of at least one chemotherapeutic agent selected from the group consisting of lomustine, a platinum-containing chemotherapeutic agent, vincristine, and cyclophosphamide.
  • the method can also further comprise administering a therapeutically effective quantity of a tyrosine kinase inhibitor or an EGFR inhibitor.
  • the method further comprises the step of administering a therapeutically effective dose of ionizing radiation
  • suitable parameters for administration of the ionizing radiation are as described above, including dosages, administration of the ionizing radiation in a single dose or in fractionated doses, and the specific type of ionizing radiation administered.
  • the method can further comprise administering to the patient a therapeutically effective quantity of an agent that suppresses the growth of cancer stem cells.
  • an agent that suppresses the growth of cancer stem cells are described above.
  • the substituted hexitol derivative such as dianhydrogalactitol substantially suppresses the growth of cancer stem cells (CSCs).
  • CSCs cancer stem cells
  • the suppression of the growth of cancer stem cells is at least 50%.
  • the suppression of the growth of cancer stem cells is at least 99%.
  • the substituted hexitol derivative such as dianhydrogalactitol is effective in suppressing the growth of cancer cells possessing O 6 -methylguanine-DNA methyltransferase (MGMT)-driven drug resistance.
  • the substituted hexitol derivative such as dianhydrogalactitol is also effective in suppressing the growth of cancer cells resistant to temozolomide.
  • the method can further comprise the administration of a therapeutically effective quantity of a tyrosine kinase inhibitor as described above.
  • the method can further comprise the administration of a therapeutically effective quantity of an epidermal growth factor receptor (EGFR) inhibitor as described above.
  • EGFR epidermal growth factor receptor
  • the EGFR inhibitor can affect either wild-type binding sites or mutated binding sites, including EGFR Variant III, as described above.
  • the method can further comprise administering to the patient a therapeutically effective quantity of an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier.
  • the method can further comprise administering to the patient a therapeutically effective quantity of an agent to counteract myelosuppression.
  • NSCLC non-small cell lung cancer
  • TKIs Tyrosine Kinase Inhibitors
  • erlotinib erlotinib
  • platinum-based regimens e.g. cisplatin
  • TKIs have resulted in vastly improved outcomes for patients with EGFR mutations; however, TKI resistance has emerged as a significant unmet medical need, and long-term prognosis with platinum-based therapies is poor. Additionally, the incidence of brain metastases is high in patients with NSCLC with a poor prognosis.
  • Dianhydrogalactitol is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks at targeting N 7 of guanine, thus differing in mechanism of action from TKIs and cisplatin. Dianhydrogalactitol further crosses the blood-brain barrier and accumulates in tumor tissue. Dianhydrogalactitol has demonstrated activity against NSCLC in preclinical and clinical trials, both as a single agent and in combination with other treatment regimens, suggesting dianhydrogalactitol may be a therapeutic option for drug-resistant NSCLC and NSCLC patients with brain metastasis.
  • mice bearing subcutaneous human lung adenocarcinoma xenograft tumors of either TKI-resistant (H1975) or TKI-sensitive (A549) origin were treated.
  • mice Two human NSCLC cell lines, A549 (TKI-sensitive) and H1975 (TKI-resistant), were used as xenograft tumor models in female Rag2 mice. The mice were 6 to 8 weeks of age and weighed 18-23 grams. 10 mice were used per group. The results reported below are for the A549 NSCLC cell line.
  • Cisplatin was used in normal saline at a dose of 5 mg/kg. Administration was intravenous.
  • Dianhydrogalactitol was used in 0.9% sodium chloride for injection at 1.5 mg/kg to 6 mg/kg. Administration was intraperitoneal.
  • Treatment was initiated at a tumor volume of 100 mm 3 to 150 mm 3 .
  • the A549 human lung carcinoma cell line had been obtained from the American Type Culture Collection (Cat. # CCL-185).
  • the cells were started from a frozen vial of lab stock that were frozen down from the ATCC original vial and kept in liquid nitrogen. Cell cultures with a passage number of 3 to 10 and a confluence of 80%-90% were used. Cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum and 2 mL L-glutamine at 37° C. in 5% CO 2 environment. Cells were subcultured once weekly with a split ratio 1:3 to 1:8 and expanded.
  • the cells were rinsed briefly once with Hanks Balanced Salt Solution without calcium or magnesium. Fresh trypsin/EDTA solution (0.25% trypsin with tetrasodium EDTA) was added, the flask was laid horizontally to ensure that the cells were covered by trypsin/EDTA, and the extra trypsin/EDTA was aspirated. The cells were allowed to sit at 37° C. for a few minutes. The cells were observed under an inverted microscope until the cell layer was dispersed, fresh medium was added, 50 ⁇ L of cell suspension was taken and mixed with trypan blue (1:1), and the cells were counted and cell viability assessed by using Cellometer Auto T4.
  • Fresh trypsin/EDTA solution 0.25% trypsin with tetrasodium EDTA
  • the cells were centrifuged at 200 ⁇ g for 7 minutes and the supernatant was aspirated. The cells were resuspended in growth medium to obtain a concentration of 100 ⁇ 10 6 cells/mL. For inoculation, 5 ⁇ 10 6 cells were used in an injection volume of 50 ⁇ L per mouse in 1:1 MatrigelTM.
  • tumor cells were implanted subcutaneously into mice in a volume of 50 ⁇ L in MatrigelTM using a 28-gauge needle; injection of the tumor cells was in the back of the mice. Mice were randomly assigned to groups based on tumor volume. The means of the tumor volumes prior at the time of randomization were 89.15 mm 3 , 86.08 mm 3 , 95.49 mm 3 , 87.15 mm 3 and 81.76 mm 3 for groups 1-5, respectively.
  • Dianhydrogalactitol was provided as a lyophilized product at 40 mg of DAG per vial.
  • DAG Dianhydrogalactitol
  • USP saline
  • mice were injected with the required volume to administer the prescribed dose (mg/kg) to the animals based on individual mouse weights using a 28-gauge needle.
  • the injection volume was 200 ⁇ L for a 20-g mouse.
  • the mice were briefly (less than 30 seconds) restrained during intravenous injections. Dilation of the vein for intravenous injections was achieved by holding the animals under a heat lamp for a period of between 1-2 minutes.
  • mice were individually weighed and injected intraperitoneally according to body weight at the specified injection concentration (see Table 1).
  • the injection volume was based on 200 ⁇ L per 20-g mouse.
  • the abdominal surface was wiped down with 70% isopropyl alcohol to clean the injection site.
  • Tumor growth was monitored by measuring tumor dimensions with calipers beginning on the first day of treatment. Tumor length and width measurements were obtained each Monday, Wednesday, and Friday. Tumor volumes were calculated according to the equation L ⁇ W 2 /2 with the length (in mm) being defined as the longer axis of the tumor. Animals were weighed at the time of tumor measurement. Tumors were allowed to grow to a maximum of 800 mm 3 before termination.
  • Cisplatin 5.0 10 20.0 0.500 0.200 3.00 1.500 1.500 1.500 Control
  • FIG. 1 shows body weight on the y-axis versus days post-inoculation on the x-axis.
  • • is the untreated control; ⁇ is the cisplatin control; ⁇ is dianhydrogalactitol at 1.5 mg/kg; ⁇ is dianhydrogalactitol at 3.0 mg/kg; and ⁇ is dianhydrogalactitol at 6.0 mg/kg.
  • FIG. 2 shows the tumor volume (means ⁇ S.E.M.) for the A549 tumor-bearing female Rag2 mice with tumor volume on the y axis versus days post-inoculation on the x-axis.
  • the top panel of FIG. 2 represents all mice for the complete duration of the study.
  • the bottom panel of FIG. 2 represents all mice until day 70 (last day for untreated control group).
  • mice were administered with untreated control (group 1), Cisplatin at 5 mg/kg Q7D ⁇ 3 i.v. (group 2) or dianhydrogalactitol at 1.5 mg/kg i.p. (group 3), 3 mg/kg (group 4), and 6 mg/kg (group 5) Monday, Wednesday, Friday for 3 weeks and tumor volume was measured 3 ⁇ weekly and summarized in FIG. 2 .
  • the top panel indicates tumor volume for all animals and the bottom panel shows results for animal until day 70. Note that the number of animals remaining on study on day 70 was 2/10 (group 1), 6/10 (group 2), 7/10 (group 3), 6/10 (group 4) and 8/10 (group 5).
  • a mean tumor volume of 200 mm 3 was observed on days 43, 49, 45, 42 and 54, respectively.
  • a mean tumor volume of 400 mm 3 was reached on days 56, 66, 67 and 81 respectively.
  • the doubling times for groups 1-4 were 13, 17, 22 and 39, respectively.
  • a tumor growth delay of 26 days was observed in animals administered 3 mg/kg dianhydrogalactitol compared to untreated controls.
  • the positive control of 5 mg/kg cisplatin had a tumor growth delay of only 4 days in comparison.
  • dianhydrogalactitol at 6 mg/kg resulted in significant weight loss and morbidity of the mice and only 3 of the 9 scheduled doses were administered.
  • the 5 mg/kg dose of cisplatin may also be near the MTD as 1 mouse was unable to receive the last dose.
  • TMZ temozolomide
  • XRT radiation
  • dianhydrogalactitol (“VAL-083”)
  • VAL-083 The N7 alkylating agent, dianhydrogalactitol
  • VAL-083 The N7 alkylating agent, dianhydrogalactitol (“VAL-083”)
  • VAL-083 dianhydrogalactitol
  • TMZ cancer stem cells
  • VAL refers to dianhydrogalactitol
  • XRT refers to radiation
  • CSC cancer stem cells
  • non-CSC refers to non-cancer-stem cell cultures.
  • dianhydrogalactitol (“VAL-083”) is shown in FIG. 3 .
  • FIG. 4 shows the MGMT status of the cultures.
  • GPDH refers to glyceraldehyde-3-phosphate dehydrogenase as a control.
  • CSCs were cultured in NSA media supplemented with B27, EGF and bFGF.
  • Non-CSCs were grown in DMEM:F12 with 10% FBS.
  • MGMT methylation and protein expression analysis of each culture was characterized.
  • TMZ or VAL-083 was added to the cultures in the indicated concentrations.
  • cells were also irradiated with 2 Gy in a Cesium irradiator.
  • cell cycle analysis was performed with Propidium Iodide staining and FACs analysis.
  • FIG. 4 Panel C shows the methylation status of MGMT for cell lines SF7996, SF8161, SF8279, and SF8565; “U” refers to unmethylated and “M” refers to methylated.
  • “1° GBM” refers to primary glioblastoma multiforme cell cultures.
  • FIG. 4 shows MGMT western blot analysis of protein extracts from 4 pairs of CSC and non-CSC cultures derived from primary GBM tissue.
  • FIG. 5 shows that dianhydrogalactitol (“VAL-083”) was better than TMZ for inhibiting tumor cell growth and that this occurred in an MGMT-independent manner.
  • FIG. 6 shows schematics of various treatment regimens for temozolomide (“TMZ”) or dianhydrogalactitol (“VAL”), with or without radiation (“XRT”).
  • TMZ temozolomide
  • VAL dianhydrogalactitol
  • XRT radiation
  • FIG. 7 shows cell cycle analyses for cancer stem cells (CSC) treated with TMZ or dianhydrogalactitol (“VAL-083”), for 7996 CSC, 8161 CSC, 8565 CSC, and 8279 CSC.
  • CSC cancer stem cells
  • VAL-083 dianhydrogalactitol
  • FIG. 8 shows cell cycle analyses for non-stem-cell cultures treated with TMZ or dianhydrogalactitol (“VAL-083”), for 7996 non-CSC, 8161 non-CSC, 8565 non-CSC, and U251.
  • VAL-083 TMZ or dianhydrogalactitol
  • FIG. 9 shows examples of FACS profiles for 7996 non-CSC dianhydrogalactitol (“VAL”) treatment.
  • dianhydrogalactitol appears to cause cell death at lower concentrations than temozolomide. Odd cell cycle profiles appear in some cultures; in some cases, there is a dip in G1 at a small dianhydrogalactitol dose (1-5 ⁇ M) and then G1 appears to recover at a larger dose (100 ⁇ M). The activity of dianhydrogalactitol is not affected by MGMT status or the stem-cell or non-stem-cell status of the culture.
  • FIG. 10 shows a schematic of the treatment regimen using either temozolomide (“TMZ”) or dianhydrogalactitol (“VAL”) and radiation (“XRT”).
  • TMZ temozolomide
  • VAL dianhydrogalactitol
  • XRT radiation
  • FIG. 11 shows results for 7996 CSC for TMZ only, VAL only, and TMZ or VAL with XRT.
  • TMZ “-D/-” indicates DMSO only (vehicle)
  • -T/- indicates TMZ only
  • -D/X or “-T/X” indicate DMSO or TMZ with XRT.
  • VAL “—P/-” indicates phosphate buffered saline (PBS) only (vehicle)
  • —V/-” indicates VAL only
  • “—P/X” or “—V/X” indicate PBS or VAL with XRT.
  • PBS phosphate buffered saline
  • FIG. 11 shows cell cycle analysis where G2 is shown at the top, S in the middle, and G1 at the bottom; both 4- and 6-day results are shown, with the 4-day results (“D4”) presented to the left of the 6-day results (“D6”).
  • D4 4-day results
  • D6 6-day results
  • the right side of FIG. 11 shows the results for cell viability as a percentage of control for D4 and D6.
  • FIG. 12 shows results for 8161 CSC depicted as in FIG. 11 .
  • FIG. 13 shows results for 8565 CSC depicted as in FIG. 11 .
  • FIG. 14 shows results for 7996 non-CSC depicted as in FIG. 11 .
  • FIG. 15 shows results for U251 depicted as in FIG. 11 .
  • FIG. 16 shows that dianhydrogalactitol causes cell cycle arrest in TMZ-resistant cultures.
  • TMZ dianhydrogalactitol
  • VAL-083 dianhydrogalactitol
  • FIG. 17 shows that dianhydrogalactitol decreases cell viability in TMZ-resistant cultures.
  • TMZ 50 ⁇ M
  • VAL-083 dianhydrogalactitol
  • FIG. 17 Shown are cell cycle profile analysis at day 4 post treatment (A,C) and cell viability analysis at day 6 post treatment (B,D) for the paired CSC (A,B) and non-CSC (C,D) 7996 culture. Whereas these cultures are not very sensitive to TMZ, they are to VAL-083.
  • FIG. 18 shows that dianhydrogalactitol acts as a radiosensitizer in primary CSC cultures.
  • dianhydrogalactitol (“VAL-083”) was added to primary CSC cultures at various doses (1, 2.5 and 5 ⁇ M) with or without irradiation (2 Gy). Shown are cell cycle profile analysis at day 4 post treatment (A,C) and cell viability analysis at day 6 post treatment (B,D) for two different patient-derived CSC cultures, 7996 (A,B) and 8565 (C,D).
  • Temozolomide was added for 3 hours and then washed out. Dianhydrogalactitol was left on for the duration of the treatment. These experiments were performed to determine the results if temozolomide was left on indefinitely or if dianhydrogalactitol was washed out after 3 hours.
  • FIG. 19 shows the treatment regimens with a wash or no wash for both dianhydrogalactitol and temozolomide.
  • FIG. 20 shows the results for 7996 GNS, showing cell cycle analysis where G2 is shown at the top, S in the middle, and G1 at the bottom. Results for TMZ are shown on the top and results for dianhydrogalactitol on the bottom. Results with a wash are shown on the left and results without a wash are shown on the right.
  • FIG. 21 shows the results for 8279 GNS, depicted as in FIG. 20 .
  • FIG. 22 shows the results for 7996 ML, depicted as in FIG. 20 .
  • FIG. 23 shows the results for 8565 ML, depicted as in FIG. 20 .
  • temozolomide did not appear to have any more effect if left on for longer than 3 hours. Dianhydrogalactitol had less effect when washed out after 3 hours.
  • FIG. 24 shows the treatment regimens for combining dianhydrogalactitol (“VAL”) and radiation (“XRT”).
  • FIG. 25 shows the results for 7996 GNS (CSC) when dianhydrogalactitol is combined with radiation. Results are shown at day 4 (“D4”) on the top and day 6 (“D6”) on the bottom.
  • the left side shows cell cycle analysis where G2 is shown at the top, S in the middle, and G1 at the bottom.
  • the right side shows cell viability at D4 and D6.
  • FIG. 26 shows the results for 8565 GNS (CSC) as depicted in FIG. 25 .
  • FIG. 27 shows the results for 7996 ML (non-CSC) as depicted in FIG. 25 .
  • FIG. 28 shows the results for 8565 ML (non-CSC) as depicted in FIG. 25 .
  • dianhydrogalactitol results in cell cycle arrest and loss of cell viability in nearly all cultures tested. Dianhydrogalactitol appears to cause cell cycle arrest and loss of cell viability at lower concentrations than temozolomide. Furthermore, the efficacy of dianhydrogalactitol is not affected by MGMT status or cell culture condition (stem versus non-stem) as all primary cultures tested were sensitive to dianhydrogalactitol exposure. For all cultures tested, a potential additive effect of dianhydrogalactitol with radiation was seen, particularly at low concentrations of dianhydrogalactitol, such as 1 ⁇ L. This was most pronounced in 7996 GNS (CSC) with 20% reduction in cell viability. These results suggest that dianhydrogalactitol may provide a greater clinical benefit to glioma patients compared to the standard of care chemotherapy, temozolomide.
  • GBM glioblastoma multiforme
  • CNS Central Nervous System
  • Front-line systemic therapy is temozolomide but resistance due to O 6 -methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor outcomes. Such resistance vastly reduces survival.
  • MGMT O 6 -methylguanine-DNA-methyltransferase
  • Dianhydrogalactitol is a first-in-class bifunctional N 7 DNA-alkylating agent that readily crosses the blood-brain barrier and accumulates in brain tissue. Dianhydrogalactitol causes interstrand DNA crosslinks at the N 7 -guanine (E. Institóris et al., “Absence of Cross-Resistance Between Two Alkylating Agents: BCNU vs. Bifunctional Galactitol,” Cancer Chemother. Pharmacol. 24:311-313 (1989), incorporated herein by this reference), which is distinct from the mechanisms of other alkylating agents used in GBM. The use of dianhydrogalactitol as an antineoplastic agent has been described in L.
  • dianhydrogalactitol demonstrated activity in pediatric and adult GBM cell lines, as well as GBM cancer stem cells.
  • dianhydrogalactitol can overcome resistance attributable to MGMT activity in vitro.
  • Dose limiting toxicity is expected to be myelosuppression, the management of which has improved in recent years.
  • MGMT O 6 -methylguanine methyltransferase
  • TMZ temozolomide
  • the cumulative dose in a 33 day cycle ranges from 9 mg/m 2 (cohort 1) to 240 mg/m 2 (cohort 7).
  • Five dose cohorts, with the highest 33 day cycle cumulative dose of 120 mg/m 2 have completed the trial with no drug-related serious adverse events: MTD was not yet reached.
  • Enrollment for cohort 6 (33 day cumulative dose: 180 mg/m 2 ) has been initiated.
  • the final cohort of this study, cohort 7 (33 day cumulative dose: 240 mg/m 2 ) will be initiated subject to no dose-limiting toxicity (DLT) in cohort 6; the results will determine the design of the safety and efficacy registration trial.
  • DLT dose-limiting toxicity
  • Phase II additional patients will be treated at the MTD (or other selected optimum Phase II dose) to measure tumor responses. All patients enrolled have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and TMZ, unless contraindicated. For these studies, the following is a summary of the inclusion criteria: (1) Patients must be greater than or equal to 18 years old. (2) There is a histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma), now recurrent, or progressive secondary brain tumor, the patient has failed standard brain radiotherapy, and the patient has brain tumor progression after at least one line of systemic therapy.
  • glioblastoma glioblastoma
  • the patient had undergone prior treatment with prolifeprospan 20 with carmustine wafer (Gliadel® wafer) within 60 days prior to first treatment (Day 0).
  • the patient had undergone prior treatment with intracerebral agents.
  • the patient shows evidence of recent hemorrhage on baseline MRI of the brain.
  • the patient is being administered concomitant medications that are strong inhibitors of cytochrome P450 and CYP3A up to 14 days before Cycle 1, Day 1 (pimozide, diltiazem, erythromycin, clarithromycin, and quinidine, and amiodarone up to 90 days before.
  • Tumor volume is measured after every second cycle and patients exhibiting any evidence of continued progression at any time during the study are discontinued, but cycle 1 toxicity is captured for MTD determination. In this design, it is not possible to perform a rigorous assessment of patient benefit due to slowed tumor growth. Tumor volume is assessed during the study based on RANO criteria. Two patients exhibiting a response (stable disease or partial response) reported in early cohorts improved clinical signs with a maximum response of 28 cycles (84 weeks) prior to discontinuing due to adverse events unrelated to study. To date, one of two patients in cohort 6 (30 mg/m 2 ) exhibited stable disease after 1 cycle of treatment. Outcomes analysis of cohort 6 is ongoing. These preliminary data support continued exploration of higher dose cohorts.
  • FIG. 29 shows the activity of dianhydrogalactitol (VAL-083) and temozolomide (TMZ) in MGMT negative pediatric human GBM cell line SF188 (first panel), MGMT negative human GBM cell line U251 (second panel) and MGMT positive human GBM cell line T98G (third panel); immunoblots showing detection of MGMT and actin (as a control) in the individual cell lines are shown under the table providing the properties of the cell lines.
  • VAL-083 dianhydrogalactitol
  • TMZ temozolomide
  • Dianhydrogalactitol was better than TMZ for inhibiting tumor growth in GBM cell lines SF188, U251, and T98G, activity independent of MGMT ( FIG. 29 ). Dianhydrogalactitol furthermore inhibited the growth of cancer stem cells (BT74, GBM4 and GBM8) by 80-100% in neurosphere growth assays, with minimal effect on normal human neural stem cells (K. Hu et al., “VAL083, a Novel N7 Alkylating Agent, Surpasses Temozolomide Activity and Inhibits Cancer Stem Cells Providing a New Potential Treatment Option for Glioblastoma Multiforme,” Cancer Res. 72(8) Suppl. 1: 1538 (2012), incorporated herein by this reference).
  • Pharmacokinetic analyses show dose-dependent systemic exposure with a short plasma 1-2 h half-life; average C max at 20 mg/m 2 is 266 ng/mL (0.18 ⁇ g/mL or ⁇ 1.8 ⁇ M). Pharmacokinetic analyses of cohort 6 (30 mg/m 2 ) are ongoing. In previous clinical trials using less sensitive bioanalytical methods than today's LC-MS-MS method (R. T. Eagan et al., “Clinical and Pharmacologic Evaluation of Split-Dose Intermittent Therapy with Dianhydrogalactitol,” Cancer Treat. Rep.
  • FIG. 30 shows the plasma concentration-time profiles of dianhydrogalactitol showing dose-dependent systemic exposure (mean of 3 subjects per cohort).
  • Table 6 shows a comparison of historical clinical data for dianhydrogalactitol in comparison with other therapies.
  • Table 7 is a table summarizing the dosing schedule for the trial reported in this Example.
  • dianhydrogalactitol shows activity against recurrent glioblastoma multiforme that has proven resistant to previous treatment with temozolomide or bevacizumab.
  • Dianhydrogalactitol also shows activity against progressive secondary brain tumors, including tumors that arise from metastases of breast adenocarcinoma, small-cell lung carcinoma, or melanoma.
  • Dianhydrogalactitol therefore provides a new treatment modality for treatment of these malignancies of the central nervous system, especially in circumstances where the malignancies have proven resistant to therapeutic agents such as temozolomide or bevacizumab.
  • dianhydrogalactitol had previously demonstrated promising clinical activity against newly-diagnosed and recurrent GBM in historical NCI-sponsored clinical trials.
  • Dianhydrogalactitol has potent MGMT-independent cytotoxic activity against GBM cell lines in vitro.
  • Pharmacokinetic analyses show dose-dependent increase in exposure with a short plasma 1-2 h half-life and a C max of ⁇ 265 ng/mL (1.8 ⁇ M) at 20 mg/m 2 (see FIG. 2 ).
  • the pharmacokinetic data is consistent with literature from previous trials, suggesting activity of dianhydrogalactitol in brain tumors; plasma concentration achieved in the 20 mg/m 2 cohort is sufficient to inhibit glioma cell growth in vitro.
  • Dianhydrogalactitol therapy is well tolerated to date; no drug-related serious adverse events have been detected.
  • the maximum tolerate dose (MTD) has not been reached after completion of cohort 6 (30 mg/m 2 ); enrollment and analysis of cohort 7 (40 mg/m 2 ) is ongoing.
  • patients with secondary brain tumors are likely more prone to myelosuppression and may have a different MTD (maximum tolerated dose) than patients with GBM. This can be determined by assessing function of the immune system and monitoring possible myelosuppression.
  • the present invention provides improved methods and compositions employing dianhydrogalactitol for the treatment of non-small-cell lung carcinoma (NSCLC), a type of lung cancer that has proven resistant to chemotherapy by conventional means.
  • NSCLC non-small-cell lung carcinoma
  • the present invention also provides improved methods and compositions employing dianhydrogalactitol for the treatment of glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • dianhydrogalactitol to treat NSCLC or GBM is expected to be well tolerated and not to result in additional side effects.
  • Dianhydrogalactitol can be used together with radiation or other chemotherapeutic agents.
  • dianhydrogalactitol can be used to treat brain metastases of NSCLC and can be used to treat NSCLC in patients who have developed resistance to platinum-based therapeutic agents such as cisplatin or to tyrosine
  • compositions according to the present invention possess industrial applicability as pharmaceutical compositions, particularly for the treatment of NSCLC or GBM.

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